Abstract
Genetic studies have identified a core set of transcription factors and target genes that control the development of the neocortex, the region of the human brain responsible for higher cognition. The specific regulatory interactions between these factors, many key upstream and downstream genes, and the enhancers that mediate all these interactions remain mostly uncharacterized. We perform p300 ChIP-seq to identify over 6,600 candidate enhancers active in the dorsal cerebral wall of embryonic day 14.5 (E14.5) mice. Over 95% of the peaks we measure are conserved to human. Eight of ten (80%) candidates tested using mouse transgenesis drive activity in restricted laminar patterns within the neocortex. GREAT based computational analysis reveals highly significant correlation with genes expressed at E14.5 in key areas for neocortex development, and allows the grouping of enhancers by known biological functions and pathways for further studies. We find that multiple genes are flanked by dozens of candidate enhancers each, including well-known key neocortical genes as well as suspected and novel genes. Nearly a quarter of our candidate enhancers are conserved well beyond mammals. Human and zebrafish regions orthologous to our candidate enhancers are shown to most often function in other aspects of central nervous system development. Finally, we find strong evidence that specific interspersed repeat families have contributed potentially key developmental enhancers via co-option. Our analysis expands the methodologies available for extracting the richness of information found in genome-wide functional maps.
Highlights
IntroductionThe developing central nervous system segments into a forebrain, midbrain, hindbrain, and spinal cord [1]
Among all vertebrates, the developing central nervous system segments into a forebrain, midbrain, hindbrain, and spinal cord [1]
Progenitor cells of the ventricular zone (VZ) produce intermediate progenitor cells that migrate out of the VZ to form the subventricular and intermediate zones (SVZ-IZ); daughter cells from both areas migrate past the SVZ-IZ to form the laminar structure of the cortical plate (CP), in an inside out fashion [6,7] (Figure 1A)
Summary
The developing central nervous system segments into a forebrain, midbrain, hindbrain, and spinal cord [1]. The forebrain is further segmented into the telencephalon and diencephalon. The mature neocortex is a complex six-layered structure unique to mammals [2,3]. It has been associated with higher cognitive functions [4], and defects in this structure are the likely source for many neurologic and psychiatric diseases [5]. In development, this region consists of a layer of progenitor cells lining the ventricles called the ventricular zone (VZ). Progenitor cells of the VZ produce intermediate progenitor cells that migrate out of the VZ to form the subventricular and intermediate zones (SVZ-IZ); daughter cells from both areas migrate past the SVZ-IZ to form the laminar structure of the cortical plate (CP), in an inside out fashion [6,7] (Figure 1A)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
