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

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.

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Published Version (Please cite this version)

10.1016/j.cub.2015.01.041

Publication Info

Boyd, J Lomax, Stephanie L Skove, Jeremy P Rouanet, Louis-Jan Pilaz, Tristan Bepler, Raluca Gordân, Gregory A Wray, Debra L Silver, et al. (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 https://hdl.handle.net/10161/9492.

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Silver

Debra Lynn Silver

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 pathologies and brain evolution. We study neural progenitors, essential cells which generate neurons and are the root of brain development. We are guided by the premise that the same mechanisms at play during normal development were co-opted during evolution and when dysregulated, can cause neurodevelopmental disease.

My research program employs a multifaceted strategy to bridge developmental neurobiology, RNA biology, and evolution. 1) We investigate how cell fates are specified, by studying how progenitor divisions influence development and disease.  2) We study diverse layers of post-transcriptional regulation in neural progenitors. We investigate RNA binding proteins implicated in development and neurological disease. Using live imaging, we also investigate how sub-cellular control of mRNA localization and translation influences neural progenitors. 3) A parallel research focus is to understand how human-specific genetic changes influence species-specific brain development. Our goal is to integrate our efforts across these three major lines of research to understand the intricacies controlling brain development.


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