Human-specific evolution of GADD45g forebrain expression

GADD45g 前脑表达的人类特异性进化

• 批准号: 8312461
• 负责人: ALEXANDER A POLLEN
• 金额: $ 1.64万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-25 至 2012-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312461
• 关键词: Affect; Autistic Disorder; Beryllium; Binding; Biological Assay; Biology; Brain; Brain Neoplasms; Bromodeoxyuridine; Cell Culture Techniques; Cell Cycle; Cell Lineage; Cell Proliferation; Cell Survival; Cells; Cloning; Comparative Study; Conserved Sequence; DNA; DNA Sequence; Data; Defect; Destinations; Development; Disease; Dorsal; Down Syndrome; Down-Regulation; Elements; Embryo; Enhancers; Epilepsy; Equilibrium; Event; Evolution; Forebrain Development; Functional RNA; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Recombination; Genomics; Human; Immune; In Situ Nick-End Labeling; In Vitro; Indium; Interneurons; Knock-out; Knockout Mice; Label; LacZ Genes; Large-Scale Sequencing; Luciferases; Malignant Neoplasms; Malignant neoplasm of brain; Mammals; Molecular; Mus; Mutation; Neocortex; Nervous System Physiology; Nervous system structure; Neurons; Pan Genus; Pattern; Phenotype; Physiologic pulse; Pituitary Gland Adenoma; Population; Primates; Production; Property; Prosencephalon; Public Health; Regulation; Regulatory Element; Reporter; Research; Role; Stretching; Techniques; Telencephalon; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Genes; Tumor Suppressor Proteins; Upstream Enhancer; Work; comparative genomics; diencephalon; excitatory neuron; genome sequencing; inhibitory neuron; insight; mutant; nerve stem cell; nervous system development; neurogenesis; postnatal; progenitor; promoter; recombinase; research study; trait

DESCRIPTION (provided by applicant): The evolutionary expansion of the human neocortex required increased production of excitatory and inhibitory neurons. The balance between excitation and inhibition is critical for normal neurological function, and yet we know little about the human-specific genetic changes underlying increased neurogenesis. The recent availability of complete genome sequence from humans and a diverse range of mammals makes large scale sequence comparisons possible. Regulatory elements that are conserved in other mammals, but surprisingly missing in humans could contribute to human specific biology. Initial work on the project shows that humans have lost a forebrain specific regulatory element in zones of inhibitory interneuron production near the tumor suppressor gene GADD45g, which is specifically expressed in neural progenitors during development. GADD45g represses cell cycle in culture and GADD45g down-regulation is strongly associated with pituitary adenomas, yet the function of GADD45g in nervous system development has not yet been explored. This project will characterize in detail the neuronal lineages affected by the human specific genetic change using genetic labeling techniques in mouse stable lines expressing Cre-recombinase driven by the enhancer missing in humans. To put the mouse expression data in the context of changes in primate gene regulation, this project will also identify the upstream regulators of the DNA sequence that is missing in humans. Finally, this project will characterize how loss of the GADD45g gene affects brain development in mouse using an existing knockout line not previously analyzed for nervous system phenotypes. Collectively, these experiments will provide an in depth study of how a human- specific genetic change may contribute to specialized aspects of human brain development.

描述（由申请人提供）：人类新皮层的进化扩展需要增加兴奋性和抑制性神经元的产生。兴奋和抑制之间的平衡对于正常的神经功能至关重要，但我们对神经发生增加背后的人类特异性遗传变化知之甚少。最近人类和多种哺乳动物的完整基因组序列的可用性使得大规模序列比较成为可能。在其他哺乳动物中保守但在人类中令人惊讶地缺失的调控元件可能有助于人类特异性生物学。该项目的初步工作表明，人类在肿瘤抑制基因GADD 45 g附近的抑制性中间神经元产生区域中丢失了前脑特异性调节元件，该基因在发育过程中在神经祖细胞中特异性表达。GADD 45 g抑制培养细胞周期，GADD 45 g下调与垂体腺瘤密切相关，但GADD 45 g在神经系统发育中的功能尚未被探索。该项目将使用基因标记技术在表达由人类缺失的增强子驱动的Cre重组酶的小鼠稳定系中详细表征受人类特异性遗传变化影响的神经元谱系。为了将小鼠表达数据置于灵长类基因调控变化的背景下，该项目还将确定人类缺失的DNA序列的上游调控因子。最后，该项目将使用先前未分析神经系统表型的现有敲除系来表征GADD45g基因的缺失如何影响小鼠的大脑发育。总的来说，这些实验将提供一个深入的研究，如何人类特定的遗传变化可能有助于人类大脑发育的专门方面。