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

dc.contributor.author

Boyd, J Lomax

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Skove, Stephanie L

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Rouanet, Jeremy P

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Pilaz, Louis-Jan

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Bepler, Tristan

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Gordân, Raluca

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Wray, Gregory A

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Silver, Debra L

dc.coverage.spatial

England

dc.date.accessioned

2015-02-25T18:48:48Z

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2015-02-25T20:00:02Z

dc.date.issued

2015-03-16

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.identifier

http://www.ncbi.nlm.nih.gov/pubmed/25702574

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S0960-9822(15)00073-1

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1879-0445

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https://hdl.handle.net/10161/9492

dc.language

eng

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Cell Press

dc.relation.ispartof

Curr Biol

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10.1016/j.cub.2015.01.041

dc.relation.replaces

http://hdl.handle.net/10161/9490

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10161/9490

dc.subject

Animals

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Biological Evolution

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Cell Cycle

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Enhancer Elements, Genetic

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Frizzled Receptors

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Humans

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Mice

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Mice, Inbred C57BL

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Mice, Transgenic

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Neocortex

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Neural Stem Cells

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Pan troglodytes

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Promoter Regions, Genetic

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RNA, Messenger

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Receptors, Cell Surface

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Species Specificity

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Wray, Gregory A|0000-0001-5634-5081

duke.contributor.orcid

Silver, Debra L|0000-0001-9189-844X

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

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Biology

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Biostatistics & Bioinformatics

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Cell Biology

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Computer Science

pubs.organisational-group

Duke

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Duke Cancer Institute

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Duke Institute for Brain Sciences

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Evolutionary Anthropology

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Institutes and Centers

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Institutes and Provost's Academic Units

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Molecular Genetics and Microbiology

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Neurobiology

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School of Medicine

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Trinity College of Arts & Sciences

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University Institutes and Centers

pubs.publication-status

Published

pubs.volume

25

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