51. The hominoid-specific gene TBC1D3 promotes generation of basal neural progenitors and induces cortical folding in mice
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Tieqiao Wen, Zhen-Ge Luo, Qiong-Qiong Hou, Xiaoqun Wang, Kong-Yan Wu, Yang Zhou, Ai-Li Sheng Sheng, Zhengang Yang, Xiang-Chun Ju, and Ying Jin
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0301 basic medicine ,Mouse ,QH301-705.5 ,Science ,Transgene ,Mice, Transgenic ,neural progenitors ,Biology ,hominoid-specific gene ,General Biochemistry, Genetics and Molecular Biology ,Adherens junction ,Mice ,03 medical and health sciences ,Basal (phylogenetics) ,Organ Culture Techniques ,0302 clinical medicine ,Neural Stem Cells ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,Transgenes ,Biology (General) ,Progenitor cell ,Gene ,Cell Proliferation ,Cerebral Cortex ,Genetics ,General Immunology and Microbiology ,General Neuroscience ,Electroporation ,GTPase-Activating Proteins ,General Medicine ,Human brain ,cortical folding ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Gene Knockdown Techniques ,Medicine ,Signal transduction ,Neuroglia ,030217 neurology & neurosurgery ,Neuroscience ,Research Article - Abstract
Cortical expansion and folding are often linked to the evolution of higher intelligence, but molecular and cellular mechanisms underlying cortical folding remain poorly understood. The hominoid-specific gene TBC1D3 undergoes segmental duplications during hominoid evolution, but its role in brain development has not been explored. Here, we found that expression of TBC1D3 in ventricular cortical progenitors of mice via in utero electroporation caused delamination of ventricular radial glia cells (vRGs) and promoted generation of self-renewing basal progenitors with typical morphology of outer radial glia (oRG), which are most abundant in primates. Furthermore, down-regulation of TBC1D3 in cultured human brain slices decreased generation of oRGs. Interestingly, localized oRG proliferation resulting from either in utero electroporation or transgenic expression of TBC1D3, was often found to underlie cortical regions exhibiting folding. Thus, we have identified a hominoid gene that is required for oRG generation in regulating the cortical expansion and folding. DOI: http://dx.doi.org/10.7554/eLife.18197.001, eLife digest The outer layer of the mammalian brain the cerebral cortex plays a key role in memory, attention, awareness and thought. While rodents have a smooth cortical surface, the cortex of larger mammals such as primates is organized into folds and furrows. These folds increase the amount of cortex that can fit inside the confines of the skull, and are thought to have allowed the evolution of more advanced thought processes. Mutations in various genes are likely to have contributed to the expansion and folding of the cortex. These mutations may not always have involved changes in the instructions encoded within the genes, but might instead have involved changes in the number of copies of a gene. One plausible candidate gene is TBC1D3, which is only found in the great apes and is active in the cortex. The chimpanzee genome contains a single copy of TBC1D3 whereas the human genome contains multiple copies. Ju, Hou et al. have now shown that introducing the TBC1D3 gene into mouse embryos triggers changes in the embryonic cortex. Specifically, this gene increases the number of a type of cell called the outer radial glial cell in the cortex. These cells give rise to new neurons, and are usually rare in mice but abundant in the brains of animals with a folded cortex. Additional experiments using samples of human brain tissue confirmed that TBC1D3 is required for the outer radial glial cells to form. The samples were collected from miscarried fetuses with the informed consent of the patients and following approved protocols and ethical guidelines. Finally, introducing the TBC1D3 gene into the mouse genome also gave rise to animals with a folded cortex, rather than their usual smooth brain surface. Further work is now required to identify how TBC1D3 helps to generate outer radial glial cells, and to work out how these cells cause the cortex to expand. Testing the behavior of mice with the TBC1D3 gene could also uncover the links between cortical folding and thought processes. DOI: http://dx.doi.org/10.7554/eLife.18197.002
- Published
- 2016
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