Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex.
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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.
Enhancer Elements, Genetic
Mice, Inbred C57BL
Neural Stem Cells
Promoter Regions, Genetic
Receptors, Cell Surface
Published Version (Please cite this version)10.1016/j.cub.2015.01.041
Publication InfoBepler, T; Boyd, J Lomax; Gordân, R; Pilaz, LJ; Rouanet, JP; Silver, Debra Lynn; ... Wray, Gregory Allan (2015). Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex. Curr Biol, 25(6). pp. 772-779. 10.1016/j.cub.2015.01.041. Retrieved from http://hdl.handle.net/10161/9492.
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Associate Professor of Molecular Genetics and Microbiology
How is the brain assembled and sculpted during embryonic development? Addressing this question has enormous implications for understanding neurodevelopmental disorders affecting brain size and function. In evolutionary terms, our newest brain structure is the cerebral cortex, which drives higher cognitive capacities. The overall mission of my research lab is to elucidate genetic and cellular mechanisms controlling cortical development and contributing to neurodevelopmental patho
Professor of Biology
I study the evolution of genes and genomes with the broad aim of understanding the origins of biological diversity. My approach focuses on changes in the expression of genes using both empirical and computational approaches and spans scales of biological organization from single nucleotides through gene networks to entire genomes. At the finer end of this spectrum of scale, I am focusing on understanding the functional consequences and fitness components of specific genetic variants within reg
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