Cortical Malformations: Lessons in Human Brain Development

Subramanian, Lakshmi; Calcagnotto, María Elisa; Paredes, Mercedes F.

doi:10.3389/fncel.2019.00576

Cited by 74 publications

(91 citation statements)

References 242 publications

(281 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…resulting from derangements of normal intrauterine developmental processes and involving cells implicated in the formation of the cortical mantle [59]. The pathological features depend mainly on the timing of the defect in the developmental processes and the cause, e.g., abnormal proliferation or apoptosis, differentiation, neuronal migration, or layering [63].…”

Section: Brain Mosaic 1q Triploidy As a New Defining Feature Of Some Pmgmentioning

confidence: 99%

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

Kobow

Jabari

Pieper

et al. 2020

Preprint

View full text Add to dashboard Cite

Polymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here we analyzed 26 PMG patients employing array-based DNA-methylation profiling on formalin-fixed paraffin-embedded material. A series of 62 well-characterized non-PMG cortical malformations (focal cortical dysplasia type 2a/b and hemimegalencephaly), temporal lobe epilepsy, and non-epilepsy autopsy controls was used as reference cohort. Unsupervised dimensionality reduction and hierarchical cluster analysis of DNA methylation profiles showed that PMG formed a distinct DNA methylation class. Copy number profiling from DNA methylation data identified a uniform duplication spanning the entire long arm of chromosome 1 in 7 out of 26 PMG patients, which was verified by additional fluorescence in situ hybridization analysis. In respective cases about 50% of nuclei in the center of the PMG lesion were 1q triploid. No chromosomal imbalance was seen in adjacent, architecturally normal-appearing tissue indicating mosaicism. Clinically, PMG 1q patients presented with a unilateral frontal or hemispheric PMG without hemimegalencephaly, a severe form of intractable epilepsy with seizure onset in the first months of life, and severe developmental delay. Our results show that PMG can be classified among other structural brain lesions according to their DNA methylation profile. One subset of PMG with distinct clinical features exhibits a duplication of chromosomal arm 1q.

show abstract

Section: Brain Mosaic 1q Triploidy As a New Defining Feature Of Some Pmgmentioning

confidence: 99%

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

Kobow

Jabari

Pieper

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Corticogenesis, the process by which the cerebral cortex is formed into six layers, requires a series of complex and well-coordinated developmental steps. Abnormalities in cortical development can lead to a complex set of malformations observed in cerebral development disorders, like severe intellectual disability and autism 77 . BAX/BAK DKO cerebral organoids had fewer number of deep layer neurons specifically in layers V and VI.…”

Section: Discussionmentioning

confidence: 99%

Modeling the function of BAX and BAK in early human brain development using iPSC-derived systems

et al. 2020

View full text Add to dashboard Cite

Intrinsic apoptosis relies on the ability of the BCL-2 family to induce the formation of pores on the outer mitochondrial membrane. Previous studies have shown that both BAX and BAK are essential during murine embryogenesis, and reports in human cancer cell lines identified non-canonical roles for BAX and BAK in mitochondrial fission during apoptosis. BAX and BAK function in human brain development remains elusive due to the lack of appropriate model systems. Here, we generated BAX/BAK double knockout human-induced pluripotent stem cells (hiPSCs), hiPSC-derived neural progenitor cells (hNPCs), neural rosettes, and cerebral organoids to uncover the effects of BAX and BAK deletion in an in vitro model of early human brain development. We found that BAX and BAK-deficient cells have abnormal mitochondrial morphology and give rise to aberrant cortical structures. We suggest crucial functions for BAX and BAK during human development, including maintenance of homeostatic mitochondrial morphology, which is crucial for proper development of progenitors and neurons of the cortex. Human pluripotent stem cell-derived systems can be useful platforms to reveal novel functions of the apoptotic machinery in neural development.

show abstract

“…mTOR signaling is a well-known pathway for its responsibility to not only for FXS [40], but also for ASD [51,52]. Overactivation of mTOR signaling during neurogenesis can increase protein synthesis and induce neuronal differentiation [53,54], leading to cortical malformation [55]. Several studies have explored the relationship between FMRP and mTOR signaling in the adult brain.…”

Section: Discussionmentioning

confidence: 99%

Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/ß-catenin, and mTOR signaling during corticogenesis

Kikkawa

Inada

Sasaki

et al. 2020

Preprint

View full text Add to dashboard Cite

Corticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the mouse cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 "core" genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/ß-catenin, and mTOR pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the Fmr1 knockout (Fmr1 KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.

show abstract

Cortical Malformations: Lessons in Human Brain Development

Cited by 74 publications

References 242 publications

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

Modeling the function of BAX and BAK in early human brain development using iPSC-derived systems

Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/ß-catenin, and mTOR signaling during corticogenesis

Contact Info

Product

Resources

About