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Sharp changes in gene expression levels along germinal layers distinguish the development of gyrencephaly

ABSTRACT: Gyrencephalic species develop folds in the cerebral cortex in a stereotypic manner, but the genetic mechanisms underlying this unique patterning process are unknown. We present a large-scale transcriptomic analysis of individual germinal layers in the developing cortex of the gyrencephalic ferret, comparing between regions prospective of fold and fissure. We find unique transcriptional signatures in each germinal compartment, indicating that thousands of genes are differentially expressed between regions, including ~80% of genes mutated in human cortical malformations. Regional differences result from sharp changes in gene expression levels, which occur at multiple locations across the developing cortex of ferret and human, but not in the lissencephalic mouse. These complex expression patterns emerge sequentially during development and map the eventual location of specific folds and fissures. Our findings demonstrate that step-wise gene expression maps within germinal layers distinguish the development of gyrencephaly from lissencephaly, and may contribute to identify novel genes responsible for human malformations.

ORGANISM(S): Mustela putorius furo

PROVIDER: GSE60687 | GEO | 2015/05/21

SECONDARY ACCESSION(S): PRJNA259289

REPOSITORIES: GEO

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Project description:Our brains accommodate a largely folded cerebral cortex that associates to our advanced brain functions. Several theories have been proposed to explain the cortical folding process, reasoning the mechanical forces as neuronal tension in underlying layers, cellular expansion and glial progenitor’s diversity in the OSVZ; but the mechanistic insights and underlying genomics changes causing the appearance of cortical folds is still illusive. Importantly, no studies have attempted to comprehensively characterize the gene regulatory networks underlying cortical folding during development. Here, by using ferret as a model system, we have compared the transcriptomes of germinal layers between sulci and gyri, of different cortical areas and across two developmental stages (E30 & E34), to achieve a comprehensive understanding of the spatio-temporal dynamics of gene expression of cortical progenitors. Furthermore, we have also characterized the epigenetic landscape of germinal layers at E30 and E34, a critical period for their development, to correlate changes in chromatin at promoter and enhancer regions with the observed changes in gene expression. Our preliminary results indicate towards a clear transformational axis of gene regulation between germinal layers. By performing motif analysis of differentially expressed gene (DEGs), we reveal transcription factors which might have a critical role in determining cortical folding. The genes targeted by these factors belong to important pathways implicated in proliferation and neurogenesis. We highlight potential candidates in cortical folding through functional validation studies and acetylation (H3K27ac) levels for these genes correlate with their expression state. Importantly, these are critical for cell adhesion, migration and proliferation processes in-line with previous studies stating that proliferative divisions cause neocortical expansions. Our findings will have strong impact on the clinical interventions for neurological disorders relating to cortical malformation, while at the same time enhancing our understanding of molecular circuitry underlying gyrencephalic brain development and folding.

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Sharp changes in gene expression levels along germinal layers distinguish the development of gyrencephaly

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