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Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex.

dc.contributor.author Bepler, T
dc.contributor.author Boyd, J Lomax
dc.contributor.author Gordân, R
dc.contributor.author Pilaz, LJ
dc.contributor.author Rouanet, JP
dc.contributor.author Silver, Debra Lynn
dc.contributor.author Skove, SL
dc.contributor.author Wray, Gregory Allan
dc.coverage.spatial England
dc.date.accessioned 2015-02-25T18:48:48Z
dc.date.accessioned 2015-02-25T20:00:02Z
dc.date.issued 2015-03-16
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/25702574
dc.identifier S0960-9822(15)00073-1
dc.identifier.uri http://hdl.handle.net/10161/9492
dc.description.abstract The human neocortex differs from that of other great apes in several notable regards, including altered cell cycle, prolonged corticogenesis, and increased size [1-5]. Although these evolutionary changes most likely contributed to the origin of distinctively human cognitive faculties, their genetic basis remains almost entirely unknown. Highly conserved non-coding regions showing rapid sequence changes along the human lineage are candidate loci for the development and evolution of uniquely human traits. Several studies have identified human-accelerated enhancers [6-14], but none have linked an expression difference to a specific organismal trait. Here we report the discovery of a human-accelerated regulatory enhancer (HARE5) of FZD8, a receptor of the Wnt pathway implicated in brain development and size [15, 16]. Using transgenic mice, we demonstrate dramatic differences in human and chimpanzee HARE5 activity, with human HARE5 driving early and robust expression at the onset of corticogenesis. Similar to HARE5 activity, FZD8 is expressed in neural progenitors of the developing neocortex [17-19]. Chromosome conformation capture assays reveal that HARE5 physically and specifically contacts the core Fzd8 promoter in the mouse embryonic neocortex. To assess the phenotypic consequences of HARE5 activity, we generated transgenic mice in which Fzd8 expression is under control of orthologous enhancers (Pt-HARE5::Fzd8 and Hs-HARE5::Fzd8). In comparison to Pt-HARE5::Fzd8, Hs-HARE5::Fzd8 mice showed marked acceleration of neural progenitor cell cycle and increased brain size. Changes in HARE5 function unique to humans thus alter the cell-cycle dynamics of a critical population of stem cells during corticogenesis and may underlie some distinctive anatomical features of the human brain.
dc.language eng
dc.relation.ispartof Curr Biol
dc.relation.isversionof 10.1016/j.cub.2015.01.041
dc.relation.replaces http://hdl.handle.net/10161/9490
dc.relation.replaces 10161/9490
dc.subject Animals
dc.subject Biological Evolution
dc.subject Cell Cycle
dc.subject Enhancer Elements, Genetic
dc.subject Frizzled Receptors
dc.subject Humans
dc.subject Mice
dc.subject Mice, Inbred C57BL
dc.subject Mice, Transgenic
dc.subject Neocortex
dc.subject Neural Stem Cells
dc.subject Pan troglodytes
dc.subject Promoter Regions, Genetic
dc.subject RNA, Messenger
dc.subject Receptors, Cell Surface
dc.subject Species Specificity
dc.title Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/25702574
pubs.begin-page 772
pubs.end-page 779
pubs.issue 6
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biology
pubs.organisational-group Biostatistics & Bioinformatics
pubs.organisational-group Cell Biology
pubs.organisational-group Computer Science
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Institute for Brain Sciences
pubs.organisational-group Evolutionary Anthropology
pubs.organisational-group Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Neurobiology
pubs.organisational-group School of Medicine
pubs.organisational-group Trinity College of Arts & Sciences
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published
pubs.volume 25
dc.identifier.eissn 1879-0445


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