RARE DISEASE
Non-syndromic cerebral malformation due to abnormal neuronal migration
Non-syndromic cerebral malformation due to abnormal neuronal migration
Non-syndromic cerebral malformation due to abnormal neuronal migration
Synonyms: Brain malformation due to abnormal neuronal migration
Synonyms: Brain malformation due to abnormal neuronal migration
Synonyms: Brain malformation due to abnormal neuronal migration
Drug discovery
220
papers
On emerging therapies
Overview
Non-syndromic cerebral malformations due to abnormal neuronal migration are structural brain defects caused by disrupted embryonic neuron migration, leading to cortical dysplasia, heterotopia, or lissencephaly. These disorders manifest with epilepsy, intellectual disability, and motor deficits, often diagnosed via neuroimaging and genetic testing [1][5][10].
Therapies
Symptomatic management: Antiseizure medications (60-70% require polytherapy), motor rehabilitation, and neurosurgical interventions (e.g., corpus callosotomy) [3][6][16].
Targeted approaches: Stereotactic radiosurgery for focal lesions; experimental therapies like mTOR inhibitors (e.g., sirolimus) and MMP-9 inhibitors (e.g., doxycycline) under investigation [8][13][18].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
220 drug discovery papers about Non-syndromic cerebral malformation due to abnormal neuronal migration. Recent publications:
220 drug discovery papers about Non-syndromic cerebral malformation due to abnormal neuronal migration. Recent publications:
categories:
Small molecules
small molecules
2025-08-06 | Altered Metabolism in Heterozygous Mice With a Mutation in the Motor Domain of Cytoplasmic Dynein, DYNC1H1 (AAA4; c9052C>T(P3018S)).
DYNC1H1 encodes the cytoplasmic dynein heavy chain, a key motor protein involved in intracellular transport and neural development. While mutations in DYNC1H1 are known to cause a range of neurodevelopmental and motor disorders, the molecular mechanisms linking genotype to phenotype remain poorly defined. Here, we investigated how a patient-derived missense mutation in the motor domain of DYNC1H1 (c.9052C>T; P3018S) affects brain metabolism and behavior using a heterozygous knock-in mouse model. Behavioral phenotyping revealed increased locomotor activity without significant changes in sociability or novelty-seeking behavior. To uncover potential molecular correlates of this hyperactive phenotype, we performed label-free quantitative proteomics on cerebrum and cerebellum tissue from male and female mice. Over 80 mitochondrial proteins exhibited differential abundance in HET mice relative to WT controls, particularly in pathways related to oxidative phosphorylation and carbohydrate metabolism. These proteomic signatures were more pronounced in the cerebrum and showed sex-specific patterns. Our findings support the hypothesis that dysregulated mitochondrial metabolism contributes to the behavioral phenotype observed in DYNC1H1 HET mice, and they provide a molecular framework for understanding how cytoplasmic dynein mutations may lead to neurodevelopmental disorders. SUMMARY: Cytoplasmic dynein is a multi-subunit motor protein complex essential for intracellular cargo transport and proper neural function. Mutations in DYNC1H1 are increasingly recognized as a cause of pediatric motor and cognitive disorders, yet the molecular underpinnings of these phenotypes are not fully understood. The P3018S mutation in DYNC1H1 disrupts the motor domain and has been associated with abnormal neuronal migration, cortical malformations, and developmental delay. In this study, we used a knock-in mouse model carrying the P3018S mutation to explore how dynein dysfunction affects brain metabolism and behavior. Our proteomic analysis of cerebrum and cerebellum samples revealed widespread differential abundance of mitochondrial proteins, particularly those involved in oxidative phosphorylation and carbohydrate metabolism. These findings align with prior behavioral and metabolic observations of increased activity and energy expenditure in heterozygous mice. By stratifying data by sex and brain region, we identified molecular patterns that may underlie the distinct neurobehavioral profiles observed in DYNC1H1-related disorders. This study provides a valuable resource linking genotype, proteomic phenotype, and behavior, and lays the groundwork for future therapeutic strategies aimed at modulating mitochondrial metabolism in affected individuals.
2025-06-17 | Dysmorphic neurons with ultralow intrinsic excitability are paradoxically hyperexcitable in neural network in a mouse model of focal cortical dysplasia type II.
Focal cortical dysplasia type II (FCDII) is one of the most common causes of refractory epilepsy. Hyperactivated mechanistic target of rapamycin (mTOR) pathway resulting from genetic mutations underlies FCDII, but it remains controversial and poorly understood whether the dysmorphic neurons play a role in cortical hyperexcitability. Here, we performed whole-cell recordings from dysmorphic neurons and nearby normal-appearing neurons in an FCDII mouse model with a PIK3CA mutation to examine intrinsic excitability and excitatory/inhibitory (E/I) synaptic inputs. To decipher the net effects of intrinsic excitability and synaptic transmission, we delivered extracellular electric stimulation to evoke action potentials (APs) and obtained the current threshold. To explore the underlying mechanisms, immunofluorescent staining was used to analyze the neuronal morphology, and rapamycin was injected into mice to suppress the activity of mTOR pathway. γ-Aminobutyric acid type B (GABAB) receptor agonist (baclofen) was applied to modulate the excitability of dysmorphic neurons. We found that dysmorphic neurons exhibited ultralow intrinsic excitability but enhanced excitatory synaptic inputs. Additionally, lower threshold intensity was required for them to evoke APs. This hyperexcitability could be attributable to mTOR-dependent increased dendritic complexity and spine density, as postnatal rapamycin application rescued these changes. Importantly, we found that activation of presynaptic GABAB receptors could specifically reduce excitatory synaptic inputs and normalize the E/I dysfunction, and thus decrease the excitability of dysmorphic neurons. Together, these findings indicate that excessive excitatory synaptic inputs prevail over reduced intrinsic excitability in dysmorphic neurons, leading to hyperexcitability in FCDII. Furthermore, they strongly suggest GABAB receptors as a potential therapeutic target for FCDII.
2025-04-07 | The response to anti-seizure medications and the development of pharmacoresistant epilepsy in malformations of cortical development.
Malformations of cortical development (MCD) are a group of congenital brain malformation disorders commonly associated with pharmacoresistant epilepsy (PRE). While studies often focus on surgery outcomes, the pharmacological treatment is still imperative and the odyssey to PRE remains underexplored. We aim to investigate the influence of anti-seizure medications (ASMs) on the development of PRE in this specific patient population. We retrospectively included a cohort of epilepsy patients with MRI-confirmed MCD due to abnormal cell proliferation and apoptosis (group I, mainly FCD II), and abnormal neuronal migration (group II, mainly heterotopia, lissencephaly, and polymicrogyria) from March 2013 to June 2023. The clinical features of group I and group II were compared. Factors associated with PRE were analyzed. The time to development of PRE with different ASMs was assessed using Kaplan-Meier survival analysis. Of 259 enrolled patients with epilepsy and MRI-confirmed MCD (group I, n = 121; group II, n = 138), 73.4% met the criteria for PRE. The median duration of follow-up from seizure onset to the last visit or surgery was 103 months (IQR 45-174), with group I showing a significantly higher PRE rate than group II (90.1% vs. 58.7%, p = 0.000). Binomial regression analysis identified the significant predictors of PRE in MCD patients: high pretreatment seizure frequency (OR = 2.506), group II patients (OR = 0.248), and failure of the first ASM (OR = 5.885). Sodium channel blockers (SCBs) were the most prescribed initial ASMs and demonstrated a higher response rate than other ASMs. Kaplan-Meier analysis revealed that using SCBs as the first ASM significantly prolongs the time to PRE, with a median of 72 months for SCB users versus 48 months for non-SCB users. Our findings indicate a high prevalence of PRE that varies among different subtypes of MCD. Early appropriate selection of ASMs, particularly SCBs, can significantly delay the time to PRE onset, offering a promising strategy for managing this complex patient population. Tailoring pharmacological approaches is crucial for optimizing outcomes, and further research is warranted to optimize treatment strategies.
2025-01-02 | Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.
Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions1. Lissencephaly ('smooth brain') spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability2. However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller-Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders.
2024-06-05 | Focal cortical dysplasia II caused by brain somatic mutation of IRS-1 is associated with ERK signaling pathway activation.
Somatic mutations have been identified in 10% to 63% of focal cortical dysplasia type II samples, primarily linked to the mTOR pathway. When the causative genetic mutations are not identified, this opens the possibility of discovering new pathogenic genes or pathways that could be contributing to the condition. In our previous study, we identified a novel candidate pathogenic somatic variant of IRS-1 c.1791dupG in the brain tissue of a child with focal cortical dysplasia type II. This study further explored the variant's role in causing type II focal cortical dysplasia through in vitro overexpression in 293T and SH-SY5Y cells and in vivo evaluation via in utero electroporation in fetal brains, assessing effects on neuronal migration, morphology, and network integrity. It was found that the mutant IRS-1 variant led to hyperactivity of p-ERK, increased cell volume, and was predominantly associated with the MAPK signaling pathway. In vivo, the IRS-1 c.1791dupG variant induced abnormal neuron migration, cytomegaly, and network hyperexcitability. Notably, the ERK inhibitor GDC-0994, rather than the mTOR inhibitor rapamycin, effectively rescued the neuronal defects. This study directly highlighted the ERK signaling pathway's role in the pathogenesis of focal cortical dysplasia II and provided a new therapeutic target for cases of focal cortical dysplasia II that are not treatable by rapamycin analogs.
gene therapies
2026-03-10 | Epilepsy-associated FOXJ3 variants link a transcriptional program of the PTEN-mTOR pathway to neuronal specification and cortical lamination.
Focal cortical dysplasia (FCD), a major cause of drug-resistant epilepsy, involves abnormal neuronal migration and cortical architecture, yet its molecular basis remains poorly defined. Here, we identify FOXJ3 pathogenic variants in patients with autosomal dominant focal epilepsy and FCD. In the developing mouse cortex, FOXJ3 declines sharply in neural progenitors after embryonic day 15.5. In utero electroporation-mediated Foxj3 knockdown in mouse brains impairs neuronal migration, disrupts cortical lamination, and alters neuronal specification, promoting upper-layer neuron production at the expense of deeper-layer neurons. ChIP-seq and scRNA-seq analyses identify Pten as a key FOXJ3 target. Notably, Pten overexpression rescues cortical defects caused by FOXJ3 deficiency. FCD-associated variant fails to upregulate Pten, leading to dysregulated mTOR signaling and enlarged neuronal soma, a hallmark of FCD. These findings suggest that mutations in FOXJ3 may cause epilepsy and FCD and define a transcriptional program that regulates the PTEN-mTOR pathway for neuronal specification and cortical lamination.
2025-02-19 | Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia.
Periventricular heterotopia (PH), a common form of gray matter heterotopia associated with developmental delay and drug-resistant seizures, poses a challenge in understanding its neurophysiological basis. Human cerebral organoids (hCOs) derived from patients with causative mutations in FAT4 or DCHS1 mimic PH features. However, neuronal activity in these 3D models has not yet been investigated. Here we show that silicon probe recordings reveal exaggerated spontaneous spike activity in FAT4 and DCHS1 hCOs, suggesting functional changes in neuronal networks. Transcriptome and proteome analyses identify changes in neuronal morphology and synaptic function. Furthermore, patch-clamp recordings reveal a decreased spike threshold specifically in DCHS1 neurons, likely due to increased somatic voltage-gated sodium channels. Additional analyses reveal increased morphological complexity of PH neurons and synaptic alterations contributing to hyperactivity, with rescue observed in DCHS1 neurons by wild-type DCHS1 expression. Overall, we provide new comprehensive insights into the cellular changes underlying symptoms of gray matter heterotopia.
2024-01-05 | An interface of genetically engineered human forebrain assembloids and polymeric nanofiber scaffolds for multiscale profiling of interneuron migration disorders
Abstract Neuronal migration is a fundamental process during brain development in which different types of neurons migrate from their place of origin to the site where they reside and make networks crucial for the formation of proper brain architecture and its overall function. Interneuron migration anomalies due to genetic or environmental perturbations can lead to malfunctions in the neural circuitry and are observed in the case of multiple neuropsychiatric conditions. Variants in Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), a member of Tyr protein kinase family and the epidermal growth factor receptor subfamily that functions as a surface receptor in interneurons, have been associated with human neurodevelopment disorders such as schizophrenia, epilepsy, and intellectual disability. Animal studies elucidate the function of ERBB4 in neuronal migration, synaptogenesis, synaptic transmission, and plasticity. However, the exact mechanistic role of ERBB4 in the migration of GABAergic cortical interneurons in humans is unidentified. In this study, we employ CRISPR/Cas9 to knockout ERBB4 in human induced pluripotent stem cells and report its effect on the phenotype and global gene expression upon deriving dorsal and ventral human forebrain identity organoids. Additionally, fluorescent reporter knock-in using CRISPR/Cas9 at an interneuron-specific marker in the same hiPS cell line allowed distinct temporal fluorescence expression in the derived ventral forebrain organoids allowing the capture of tangential migration of labeled cortical interneurons in intact fused 3D assembloids, to pinpoint the role of ERBB4 in migration and function of these neurons. To capture the changes in migration dynamics of individual ERBB4 −/− interneurons in high resolution, we recapitulated the migration behaviour. on nanofiber scaffolds that mimic the in vivo fibrous extracellular microenvironment. Our findings uncover the function of ERBB4 in the context of human interneuron migration.
2023-04-05 | Abnormal Chromatin Remodeling Caused by ARID1A Deletion Leads to Malformation of the Dentate Gyrus
Abstract ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be a tumor suppressor. Recently, loss-of-function of ARID1A gene has been shown to cause intellectual disability. Here we generate Arid1a conditional knockout mice and investigate Arid1a function in the hippocampus. Disruption of Arid1a in mouse forebrain significantly decreases neural stem/progenitor cells (NSPCs) proliferation and differentiation to neurons within the dentate gyrus (DG), increases perinatal and postnatal apoptosis, leading to reduced hippocampus size. Moreover, we perform single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and reveal that Arid1a is necessary for the maintenance of the DG progenitor pool and survival of post-mitotic neurons. Transcriptome and ChIP-seq analysis data demonstrate that ARID1A specifically regulates Prox1 by altering the levels of histone modifications. Overexpression of downstream target Prox1 can rescue proliferation and differentiation defects of NSPCs caused by Arid1a deletion. Overall, our results demonstrate a critical role for Arid1a in the development of the hippocampus and may also provide insight into the genetic basis of intellectual disabilities such as Coffin–Siris syndrome, which is caused by germ-line mutations or microduplication of Arid1a .
2022-05-20 | Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development.
Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
proteins
2024-08-15 | De novo monoallelic Reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism.
Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.
2024-04-11 | Mice Mutated in the First Fibronectin Domain of Adhesion Molecule L1 Show Brain Malformations and Behavioral Abnormalities
The X-chromosome-linked cell adhesion molecule L1 (L1CAM), a glycoprotein mainly expressed by neurons in the central and peripheral nervous systems, has been implicated in many neural processes, including neuronal migration and survival, neuritogenesis, synapse formation, synaptic plasticity and regeneration. L1 consists of extracellular, transmembrane and cytoplasmic domains. Proteolytic cleavage of L1’s extracellular and transmembrane domains by different proteases generates several L1 fragments with different functions. We found that myelin basic protein (MBP) cleaves L1’s extracellular domain, leading to enhanced neuritogenesis and neuronal survival in vitro. To investigate in vivo the importance of the MBP-generated 70 kDa fragment (L1-70), we generated mice with an arginine to alanine substitution at position 687 (L1/687), thereby disrupting L1’s MBP cleavage site and obliterating L1-70. Young adult L1/687 males showed normal anxiety and circadian rhythm activities but enhanced locomotion, while females showed altered social interactions. Older L1/687 males were impaired in motor coordination. Furthermore, L1/687 male and female mice had a larger hippocampus, with more neurons in the dentate gyrus and more proliferating cells in the subgranular layer, while the thickness of the corpus callosum and the size of lateral ventricles were normal. In summary, subtle mutant morphological changes result in subtle behavioral changes.
2024-01-09 | Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations
Abstract The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1 / NDE1 and Ndel1 / NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus–centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.
2024-01-09 | Altered Extracellular Matrix Structure and Elevated Stiffness in a Brain Organoid Model for Disease
The viscoelasticity of tissues impacts their shape, as well as the growth and differentiation of their cells. Nevertheless, little is known about changes in viscoelastic properties during brain malformations. Lissencephaly is a severe malformation of cortical development caused by LIS1 mutations, which results in a lack of cortical convolutions. Here, we show that human-derived brain organoids with LIS1 mutation are stiffer than control ones at multiple developmental times. This stiffening is accompanied by abnormal ECM expression and organization, as well as elevated water content, as measured by diffusion-weighted MRI. Proteolytic cleavage of ECM components by short-term treatment with the catalytic subunit of MMP9 reduced the stiffening and water diffusion levels of mutated organoids to control levels. Finally, based on the molecular and rheological properties obtained, we generated a computational microstructure mechanical model that can successfully predict mechanical changes that follow differential ECM localization and integrity in the developing brain. Overall, our study reveals that LIS1 is essential for the expression and organization of ECM proteins during brain development, and its mutation leads to a substantial viscoelastic change. To our knowledge, this is the first study to elucidate how tissue mechanics change in disease states using human brain organoids.
2023-07-15 | Carbamoylated Erythropoietin-Induced Cerebral Blood Perfusion and Vascular Gene Regulation
Cerebral hypoperfusion is associated with enhanced cognitive decline and increased risk of neuropsychiatric disorders. Erythropoietin (EPO) is a neurotrophic factor known to improve cognitive function in preclinical and clinical studies of neurodegenerative and psychiatric disorders. However, the clinical application of EPO is limited due to its erythropoietic activity that can adversely elevate hematocrit in non-anemic populations. Carbamoylated erythropoietin (CEPO), a chemically engineered non-erythropoietic derivative of EPO, does not alter hematocrit and maintains neurotrophic and behavioral effects comparable to EPO. Our study aimed to investigate the role of CEPO in cerebral hemodynamics. Magnetic resonance imaging (MRI) analysis indicated increased blood perfusion in the hippocampal and striatal region without altering tight junction integrity. In vitro and in vivo analyses indicated that hippocampal neurotransmission was unaltered and increased cerebral perfusion was likely due to EDRF, CGRP, and NOS-mediated vasodilation. In vitro analysis using human umbilical vein endothelial cells (HUVEC) and hippocampal vascular gene expression analysis showed CEPO to be a non-angiogenic agent which regulates the MEOX2 gene expression. The results from our study demonstrate a novel role of CEPO in modulating cerebral vasodilation and blood perfusion.
antibodies
2023-11-09 | Assembly of neuron- and radial glial cell-derived extracellular matrix molecules promotes radial migration of developing cortical neurons
Radial neuronal migration is a key neurodevelopmental event for proper cortical laminar organization. The multipolar-to-bipolar transition, a critical step in establishing neuronal polarity during radial migration, occurs in the subplate/intermediate zone (SP/IZ), a distinct region of the embryonic cerebral cortex. It has been known that the extracellular matrix (ECM) molecules are enriched in the SP/IZ. However, the molecular constitution and functions of the ECM formed in this region remain poorly understood. Here, we identified neurocan (NCAN) as a major chondroitin sulfate proteoglycan in the SP/IZ. NCAN binds to both radial glial cell-derived tenascin-C (TNC) and hyaluronan (HA), a large linear polysaccharide, forming a ternary complex of NCAN, TNC, and HA in the SP/IZ. Developing cortical neurons make contact with the ternary complex during migration. The enzymatic or genetic disruption of the ternary complex impairs radial migration by suppressing the multipolar-to-bipolar transition. Furthermore, both TNC and NCAN promoted the morphological maturation of cortical neurons in vitro. The present results provide evidence for the cooperative role of neuron- and radial glial cell-derived ECM molecules in cortical development.
2022-10-01 | GPC3-Unc5 receptor complex structure and role in cell migration
Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.
2011-12-19 | Faculty Opinions recommendation of G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination.
GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα(12/13) family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain. PMID: 21768377 Funding information This work was supported by: NINDS NIH HHS, United States Grant ID: R01 NS057536
2011-07-18 | G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination
GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1 ) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα 12/13 family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain.
2006-05-26 | Nidogen and Nidogen-Associated Basement Membrane Proteins and Neuronal Plasticity
Extracellular matrix (ECM) proteins are thought to subserve structural functions as, for example, tissue barriers as well as guidance structures during cell growth, differentiation and tissue repair. Deletion of basement membrane (BM) components results in malformations of different organs, including the brain. Recent data, however, suggest that interference with cellular membrane-associated proteins interacting with ECM can alter neuronal excitability and synaptic plasticity without obvious underlying structural damage. This does not only apply to classical ECM proteins such as laminin, reelin and tenascin, but also to molecules of a rather specialized ECM, the BM. Here, nidogen (also termed entactin) appears to subserve a function in neuronal plasticity. Nidogen ablation leads to epileptic activity in vivo and the appearance of spontaneous epileptiform activity in vitro. This raises the intriguing question whether the BM protein nidogen may directly influence neuronal function in the CNS, opening the possibility of modulatory mechanisms of synaptic plasticity and excitability reaching beyond classical processes confined to cellular interactions.
small molecules
2025-08-06 | Altered Metabolism in Heterozygous Mice With a Mutation in the Motor Domain of Cytoplasmic Dynein, DYNC1H1 (AAA4; c9052C>T(P3018S)).
DYNC1H1 encodes the cytoplasmic dynein heavy chain, a key motor protein involved in intracellular transport and neural development. While mutations in DYNC1H1 are known to cause a range of neurodevelopmental and motor disorders, the molecular mechanisms linking genotype to phenotype remain poorly defined. Here, we investigated how a patient-derived missense mutation in the motor domain of DYNC1H1 (c.9052C>T; P3018S) affects brain metabolism and behavior using a heterozygous knock-in mouse model. Behavioral phenotyping revealed increased locomotor activity without significant changes in sociability or novelty-seeking behavior. To uncover potential molecular correlates of this hyperactive phenotype, we performed label-free quantitative proteomics on cerebrum and cerebellum tissue from male and female mice. Over 80 mitochondrial proteins exhibited differential abundance in HET mice relative to WT controls, particularly in pathways related to oxidative phosphorylation and carbohydrate metabolism. These proteomic signatures were more pronounced in the cerebrum and showed sex-specific patterns. Our findings support the hypothesis that dysregulated mitochondrial metabolism contributes to the behavioral phenotype observed in DYNC1H1 HET mice, and they provide a molecular framework for understanding how cytoplasmic dynein mutations may lead to neurodevelopmental disorders. SUMMARY: Cytoplasmic dynein is a multi-subunit motor protein complex essential for intracellular cargo transport and proper neural function. Mutations in DYNC1H1 are increasingly recognized as a cause of pediatric motor and cognitive disorders, yet the molecular underpinnings of these phenotypes are not fully understood. The P3018S mutation in DYNC1H1 disrupts the motor domain and has been associated with abnormal neuronal migration, cortical malformations, and developmental delay. In this study, we used a knock-in mouse model carrying the P3018S mutation to explore how dynein dysfunction affects brain metabolism and behavior. Our proteomic analysis of cerebrum and cerebellum samples revealed widespread differential abundance of mitochondrial proteins, particularly those involved in oxidative phosphorylation and carbohydrate metabolism. These findings align with prior behavioral and metabolic observations of increased activity and energy expenditure in heterozygous mice. By stratifying data by sex and brain region, we identified molecular patterns that may underlie the distinct neurobehavioral profiles observed in DYNC1H1-related disorders. This study provides a valuable resource linking genotype, proteomic phenotype, and behavior, and lays the groundwork for future therapeutic strategies aimed at modulating mitochondrial metabolism in affected individuals.
2025-06-17 | Dysmorphic neurons with ultralow intrinsic excitability are paradoxically hyperexcitable in neural network in a mouse model of focal cortical dysplasia type II.
Focal cortical dysplasia type II (FCDII) is one of the most common causes of refractory epilepsy. Hyperactivated mechanistic target of rapamycin (mTOR) pathway resulting from genetic mutations underlies FCDII, but it remains controversial and poorly understood whether the dysmorphic neurons play a role in cortical hyperexcitability. Here, we performed whole-cell recordings from dysmorphic neurons and nearby normal-appearing neurons in an FCDII mouse model with a PIK3CA mutation to examine intrinsic excitability and excitatory/inhibitory (E/I) synaptic inputs. To decipher the net effects of intrinsic excitability and synaptic transmission, we delivered extracellular electric stimulation to evoke action potentials (APs) and obtained the current threshold. To explore the underlying mechanisms, immunofluorescent staining was used to analyze the neuronal morphology, and rapamycin was injected into mice to suppress the activity of mTOR pathway. γ-Aminobutyric acid type B (GABAB) receptor agonist (baclofen) was applied to modulate the excitability of dysmorphic neurons. We found that dysmorphic neurons exhibited ultralow intrinsic excitability but enhanced excitatory synaptic inputs. Additionally, lower threshold intensity was required for them to evoke APs. This hyperexcitability could be attributable to mTOR-dependent increased dendritic complexity and spine density, as postnatal rapamycin application rescued these changes. Importantly, we found that activation of presynaptic GABAB receptors could specifically reduce excitatory synaptic inputs and normalize the E/I dysfunction, and thus decrease the excitability of dysmorphic neurons. Together, these findings indicate that excessive excitatory synaptic inputs prevail over reduced intrinsic excitability in dysmorphic neurons, leading to hyperexcitability in FCDII. Furthermore, they strongly suggest GABAB receptors as a potential therapeutic target for FCDII.
2025-04-07 | The response to anti-seizure medications and the development of pharmacoresistant epilepsy in malformations of cortical development.
Malformations of cortical development (MCD) are a group of congenital brain malformation disorders commonly associated with pharmacoresistant epilepsy (PRE). While studies often focus on surgery outcomes, the pharmacological treatment is still imperative and the odyssey to PRE remains underexplored. We aim to investigate the influence of anti-seizure medications (ASMs) on the development of PRE in this specific patient population. We retrospectively included a cohort of epilepsy patients with MRI-confirmed MCD due to abnormal cell proliferation and apoptosis (group I, mainly FCD II), and abnormal neuronal migration (group II, mainly heterotopia, lissencephaly, and polymicrogyria) from March 2013 to June 2023. The clinical features of group I and group II were compared. Factors associated with PRE were analyzed. The time to development of PRE with different ASMs was assessed using Kaplan-Meier survival analysis. Of 259 enrolled patients with epilepsy and MRI-confirmed MCD (group I, n = 121; group II, n = 138), 73.4% met the criteria for PRE. The median duration of follow-up from seizure onset to the last visit or surgery was 103 months (IQR 45-174), with group I showing a significantly higher PRE rate than group II (90.1% vs. 58.7%, p = 0.000). Binomial regression analysis identified the significant predictors of PRE in MCD patients: high pretreatment seizure frequency (OR = 2.506), group II patients (OR = 0.248), and failure of the first ASM (OR = 5.885). Sodium channel blockers (SCBs) were the most prescribed initial ASMs and demonstrated a higher response rate than other ASMs. Kaplan-Meier analysis revealed that using SCBs as the first ASM significantly prolongs the time to PRE, with a median of 72 months for SCB users versus 48 months for non-SCB users. Our findings indicate a high prevalence of PRE that varies among different subtypes of MCD. Early appropriate selection of ASMs, particularly SCBs, can significantly delay the time to PRE onset, offering a promising strategy for managing this complex patient population. Tailoring pharmacological approaches is crucial for optimizing outcomes, and further research is warranted to optimize treatment strategies.
2025-01-02 | Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.
Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions1. Lissencephaly ('smooth brain') spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability2. However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller-Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders.
2024-06-05 | Focal cortical dysplasia II caused by brain somatic mutation of IRS-1 is associated with ERK signaling pathway activation.
Somatic mutations have been identified in 10% to 63% of focal cortical dysplasia type II samples, primarily linked to the mTOR pathway. When the causative genetic mutations are not identified, this opens the possibility of discovering new pathogenic genes or pathways that could be contributing to the condition. In our previous study, we identified a novel candidate pathogenic somatic variant of IRS-1 c.1791dupG in the brain tissue of a child with focal cortical dysplasia type II. This study further explored the variant's role in causing type II focal cortical dysplasia through in vitro overexpression in 293T and SH-SY5Y cells and in vivo evaluation via in utero electroporation in fetal brains, assessing effects on neuronal migration, morphology, and network integrity. It was found that the mutant IRS-1 variant led to hyperactivity of p-ERK, increased cell volume, and was predominantly associated with the MAPK signaling pathway. In vivo, the IRS-1 c.1791dupG variant induced abnormal neuron migration, cytomegaly, and network hyperexcitability. Notably, the ERK inhibitor GDC-0994, rather than the mTOR inhibitor rapamycin, effectively rescued the neuronal defects. This study directly highlighted the ERK signaling pathway's role in the pathogenesis of focal cortical dysplasia II and provided a new therapeutic target for cases of focal cortical dysplasia II that are not treatable by rapamycin analogs.
gene therapies
2026-03-10 | Epilepsy-associated FOXJ3 variants link a transcriptional program of the PTEN-mTOR pathway to neuronal specification and cortical lamination.
Focal cortical dysplasia (FCD), a major cause of drug-resistant epilepsy, involves abnormal neuronal migration and cortical architecture, yet its molecular basis remains poorly defined. Here, we identify FOXJ3 pathogenic variants in patients with autosomal dominant focal epilepsy and FCD. In the developing mouse cortex, FOXJ3 declines sharply in neural progenitors after embryonic day 15.5. In utero electroporation-mediated Foxj3 knockdown in mouse brains impairs neuronal migration, disrupts cortical lamination, and alters neuronal specification, promoting upper-layer neuron production at the expense of deeper-layer neurons. ChIP-seq and scRNA-seq analyses identify Pten as a key FOXJ3 target. Notably, Pten overexpression rescues cortical defects caused by FOXJ3 deficiency. FCD-associated variant fails to upregulate Pten, leading to dysregulated mTOR signaling and enlarged neuronal soma, a hallmark of FCD. These findings suggest that mutations in FOXJ3 may cause epilepsy and FCD and define a transcriptional program that regulates the PTEN-mTOR pathway for neuronal specification and cortical lamination.
2025-02-19 | Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia.
Periventricular heterotopia (PH), a common form of gray matter heterotopia associated with developmental delay and drug-resistant seizures, poses a challenge in understanding its neurophysiological basis. Human cerebral organoids (hCOs) derived from patients with causative mutations in FAT4 or DCHS1 mimic PH features. However, neuronal activity in these 3D models has not yet been investigated. Here we show that silicon probe recordings reveal exaggerated spontaneous spike activity in FAT4 and DCHS1 hCOs, suggesting functional changes in neuronal networks. Transcriptome and proteome analyses identify changes in neuronal morphology and synaptic function. Furthermore, patch-clamp recordings reveal a decreased spike threshold specifically in DCHS1 neurons, likely due to increased somatic voltage-gated sodium channels. Additional analyses reveal increased morphological complexity of PH neurons and synaptic alterations contributing to hyperactivity, with rescue observed in DCHS1 neurons by wild-type DCHS1 expression. Overall, we provide new comprehensive insights into the cellular changes underlying symptoms of gray matter heterotopia.
2024-01-05 | An interface of genetically engineered human forebrain assembloids and polymeric nanofiber scaffolds for multiscale profiling of interneuron migration disorders
Abstract Neuronal migration is a fundamental process during brain development in which different types of neurons migrate from their place of origin to the site where they reside and make networks crucial for the formation of proper brain architecture and its overall function. Interneuron migration anomalies due to genetic or environmental perturbations can lead to malfunctions in the neural circuitry and are observed in the case of multiple neuropsychiatric conditions. Variants in Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), a member of Tyr protein kinase family and the epidermal growth factor receptor subfamily that functions as a surface receptor in interneurons, have been associated with human neurodevelopment disorders such as schizophrenia, epilepsy, and intellectual disability. Animal studies elucidate the function of ERBB4 in neuronal migration, synaptogenesis, synaptic transmission, and plasticity. However, the exact mechanistic role of ERBB4 in the migration of GABAergic cortical interneurons in humans is unidentified. In this study, we employ CRISPR/Cas9 to knockout ERBB4 in human induced pluripotent stem cells and report its effect on the phenotype and global gene expression upon deriving dorsal and ventral human forebrain identity organoids. Additionally, fluorescent reporter knock-in using CRISPR/Cas9 at an interneuron-specific marker in the same hiPS cell line allowed distinct temporal fluorescence expression in the derived ventral forebrain organoids allowing the capture of tangential migration of labeled cortical interneurons in intact fused 3D assembloids, to pinpoint the role of ERBB4 in migration and function of these neurons. To capture the changes in migration dynamics of individual ERBB4 −/− interneurons in high resolution, we recapitulated the migration behaviour. on nanofiber scaffolds that mimic the in vivo fibrous extracellular microenvironment. Our findings uncover the function of ERBB4 in the context of human interneuron migration.
2023-04-05 | Abnormal Chromatin Remodeling Caused by ARID1A Deletion Leads to Malformation of the Dentate Gyrus
Abstract ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be a tumor suppressor. Recently, loss-of-function of ARID1A gene has been shown to cause intellectual disability. Here we generate Arid1a conditional knockout mice and investigate Arid1a function in the hippocampus. Disruption of Arid1a in mouse forebrain significantly decreases neural stem/progenitor cells (NSPCs) proliferation and differentiation to neurons within the dentate gyrus (DG), increases perinatal and postnatal apoptosis, leading to reduced hippocampus size. Moreover, we perform single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and reveal that Arid1a is necessary for the maintenance of the DG progenitor pool and survival of post-mitotic neurons. Transcriptome and ChIP-seq analysis data demonstrate that ARID1A specifically regulates Prox1 by altering the levels of histone modifications. Overexpression of downstream target Prox1 can rescue proliferation and differentiation defects of NSPCs caused by Arid1a deletion. Overall, our results demonstrate a critical role for Arid1a in the development of the hippocampus and may also provide insight into the genetic basis of intellectual disabilities such as Coffin–Siris syndrome, which is caused by germ-line mutations or microduplication of Arid1a .
2022-05-20 | Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development.
Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
proteins
2024-08-15 | De novo monoallelic Reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism.
Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.
2024-04-11 | Mice Mutated in the First Fibronectin Domain of Adhesion Molecule L1 Show Brain Malformations and Behavioral Abnormalities
The X-chromosome-linked cell adhesion molecule L1 (L1CAM), a glycoprotein mainly expressed by neurons in the central and peripheral nervous systems, has been implicated in many neural processes, including neuronal migration and survival, neuritogenesis, synapse formation, synaptic plasticity and regeneration. L1 consists of extracellular, transmembrane and cytoplasmic domains. Proteolytic cleavage of L1’s extracellular and transmembrane domains by different proteases generates several L1 fragments with different functions. We found that myelin basic protein (MBP) cleaves L1’s extracellular domain, leading to enhanced neuritogenesis and neuronal survival in vitro. To investigate in vivo the importance of the MBP-generated 70 kDa fragment (L1-70), we generated mice with an arginine to alanine substitution at position 687 (L1/687), thereby disrupting L1’s MBP cleavage site and obliterating L1-70. Young adult L1/687 males showed normal anxiety and circadian rhythm activities but enhanced locomotion, while females showed altered social interactions. Older L1/687 males were impaired in motor coordination. Furthermore, L1/687 male and female mice had a larger hippocampus, with more neurons in the dentate gyrus and more proliferating cells in the subgranular layer, while the thickness of the corpus callosum and the size of lateral ventricles were normal. In summary, subtle mutant morphological changes result in subtle behavioral changes.
2024-01-09 | Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations
Abstract The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1 / NDE1 and Ndel1 / NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus–centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.
2024-01-09 | Altered Extracellular Matrix Structure and Elevated Stiffness in a Brain Organoid Model for Disease
The viscoelasticity of tissues impacts their shape, as well as the growth and differentiation of their cells. Nevertheless, little is known about changes in viscoelastic properties during brain malformations. Lissencephaly is a severe malformation of cortical development caused by LIS1 mutations, which results in a lack of cortical convolutions. Here, we show that human-derived brain organoids with LIS1 mutation are stiffer than control ones at multiple developmental times. This stiffening is accompanied by abnormal ECM expression and organization, as well as elevated water content, as measured by diffusion-weighted MRI. Proteolytic cleavage of ECM components by short-term treatment with the catalytic subunit of MMP9 reduced the stiffening and water diffusion levels of mutated organoids to control levels. Finally, based on the molecular and rheological properties obtained, we generated a computational microstructure mechanical model that can successfully predict mechanical changes that follow differential ECM localization and integrity in the developing brain. Overall, our study reveals that LIS1 is essential for the expression and organization of ECM proteins during brain development, and its mutation leads to a substantial viscoelastic change. To our knowledge, this is the first study to elucidate how tissue mechanics change in disease states using human brain organoids.
2023-07-15 | Carbamoylated Erythropoietin-Induced Cerebral Blood Perfusion and Vascular Gene Regulation
Cerebral hypoperfusion is associated with enhanced cognitive decline and increased risk of neuropsychiatric disorders. Erythropoietin (EPO) is a neurotrophic factor known to improve cognitive function in preclinical and clinical studies of neurodegenerative and psychiatric disorders. However, the clinical application of EPO is limited due to its erythropoietic activity that can adversely elevate hematocrit in non-anemic populations. Carbamoylated erythropoietin (CEPO), a chemically engineered non-erythropoietic derivative of EPO, does not alter hematocrit and maintains neurotrophic and behavioral effects comparable to EPO. Our study aimed to investigate the role of CEPO in cerebral hemodynamics. Magnetic resonance imaging (MRI) analysis indicated increased blood perfusion in the hippocampal and striatal region without altering tight junction integrity. In vitro and in vivo analyses indicated that hippocampal neurotransmission was unaltered and increased cerebral perfusion was likely due to EDRF, CGRP, and NOS-mediated vasodilation. In vitro analysis using human umbilical vein endothelial cells (HUVEC) and hippocampal vascular gene expression analysis showed CEPO to be a non-angiogenic agent which regulates the MEOX2 gene expression. The results from our study demonstrate a novel role of CEPO in modulating cerebral vasodilation and blood perfusion.
antibodies
2023-11-09 | Assembly of neuron- and radial glial cell-derived extracellular matrix molecules promotes radial migration of developing cortical neurons
Radial neuronal migration is a key neurodevelopmental event for proper cortical laminar organization. The multipolar-to-bipolar transition, a critical step in establishing neuronal polarity during radial migration, occurs in the subplate/intermediate zone (SP/IZ), a distinct region of the embryonic cerebral cortex. It has been known that the extracellular matrix (ECM) molecules are enriched in the SP/IZ. However, the molecular constitution and functions of the ECM formed in this region remain poorly understood. Here, we identified neurocan (NCAN) as a major chondroitin sulfate proteoglycan in the SP/IZ. NCAN binds to both radial glial cell-derived tenascin-C (TNC) and hyaluronan (HA), a large linear polysaccharide, forming a ternary complex of NCAN, TNC, and HA in the SP/IZ. Developing cortical neurons make contact with the ternary complex during migration. The enzymatic or genetic disruption of the ternary complex impairs radial migration by suppressing the multipolar-to-bipolar transition. Furthermore, both TNC and NCAN promoted the morphological maturation of cortical neurons in vitro. The present results provide evidence for the cooperative role of neuron- and radial glial cell-derived ECM molecules in cortical development.
2022-10-01 | GPC3-Unc5 receptor complex structure and role in cell migration
Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.
2011-12-19 | Faculty Opinions recommendation of G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination.
GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα(12/13) family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain. PMID: 21768377 Funding information This work was supported by: NINDS NIH HHS, United States Grant ID: R01 NS057536
2011-07-18 | G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination
GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1 ) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα 12/13 family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain.
2006-05-26 | Nidogen and Nidogen-Associated Basement Membrane Proteins and Neuronal Plasticity
Extracellular matrix (ECM) proteins are thought to subserve structural functions as, for example, tissue barriers as well as guidance structures during cell growth, differentiation and tissue repair. Deletion of basement membrane (BM) components results in malformations of different organs, including the brain. Recent data, however, suggest that interference with cellular membrane-associated proteins interacting with ECM can alter neuronal excitability and synaptic plasticity without obvious underlying structural damage. This does not only apply to classical ECM proteins such as laminin, reelin and tenascin, but also to molecules of a rather specialized ECM, the BM. Here, nidogen (also termed entactin) appears to subserve a function in neuronal plasticity. Nidogen ablation leads to epileptic activity in vivo and the appearance of spontaneous epileptiform activity in vitro. This raises the intriguing question whether the BM protein nidogen may directly influence neuronal function in the CNS, opening the possibility of modulatory mechanisms of synaptic plasticity and excitability reaching beyond classical processes confined to cellular interactions.
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