Engrailed genes and cerebellum morphology, spatial gene expression and circuitry

纠缠基因和小脑形态、空间基因表达和电路

• 批准号: 9199242
• 负责人: ALEXANDRA L. JOYNER
• 金额: $ 63.94万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199242
• 关键词: Address; Adhesions; Affect; Affective; Afferent Pathways; Alpha Cell; Alpha Granule; Architecture; Autistic Disorder; Back; Behavior; Behavioral; Biochemical; Brain; Cell Count; Cell Cycle Regulation; Cell Lineage; Cell Proliferation; Cell Survival; Cell division; Cell physiology; Cells; Cerebellar Nuclei; Cerebellum; ChIP-seq; Complex; Cytoplasmic Granules; Defect; Development; Developmental Gene; Disease; Embryo; Emotional; Engineering; Ensure; Fissural; Funding; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Processes; Genetic Techniques; Growth; Homeobox; Human; Image; In Vitro; Knockout Mice; Language; Lip structure; Methods; Microarray Analysis; Molecular; Morphogenesis; Morphology; Mosaicism; Motor; Mouse Strains; Mus; Mutant Strains Mice; Mutate; Neurons; Output; Pathway Analysis; Pathway interactions; Patients; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Process; Production; Proteins; Purkinje Cells; Rest; Role; SHH gene; Slice; Social Behavior; Social Functioning; Sonic Hedgehog Pathway; Susceptibility Gene; Techniques; Testing; Time; autism spectrum disorder; base; behavioral study; cell behavior; cell type; cognitive function; comparative; conditional mutant; differential expression; disease diagnosis; experimental study; feeding; imaging study; in vivo; insight; live cell imaging; migration; motor control; mutant; nerve stem cell; novel; overexpression; public health relevance; smoothened signaling pathway; social; social cognition; transcription factor

DESCRIPTION (provided by applicant): The cerebellum (Cb) is implicated in contributing to cognitive and social functions, in addition to having a critical role in skilled motor performance. Accordingly, the Cb is associated with many debilitating developmental diseases including autism. One gene that regulates development of the Cb and has been implicated in autism is engrailed 2 (EN2), based on human studies and the finding that En2 null mice not only have deficits in motor control, but also in social behaviors and cognition. Before we can begin to understand higher order functions of the Cb, we must gain more insight into the basic cellular and genetic processes that regulate Cb development. Our approach is to use the two EN homeobox transcription factors as molecular entry points to study Cb development, as we discovered that En1/2 conditional mutants have defects in Cb morphology, molecular patterning and afferent circuitry. We will now direct our studies towards distinguishing the cellular processes regulated by En1/2 and identifying EN2 target genes critical for these processes that could be susceptibility loci for complex behavioral diseases. We will focus on the granule neurons (GNs) that comprise the main recipients of input to the Cb and the deep cerebellar nuclei (DCN) that generate the output. DCN neurons are consistently reduced in autistic patients, which could be a primary cause of some behaviors and also reflect defects elsewhere in the Cb circuit. We will apply a multi-facetted approach that combines novel genetic techniques in mice to study normal and mutant behaviors of GNs and DCN projection neurons, including a mosaic mutant analysis using our MASTR technique and a new method to precisely target over- expression of EN2 to GNs and the DCN to test sufficiency of EN2 to alter differentiation. We will then apply both mutant approaches to live imaging of GNs as a different approach to study Cb morphogenesis and cell proliferation/differentiation. We will also address the question of whether feed back loops ensure the correct proportion of cell types is produced by studying the interaction between En1/2 and the sonic hedgehog (SHH) pathway. Finally, in order to identify the first direct targets of EN2 in the brain, we are engineering new mouse strains expressing a tagged form of EN2. Aim 1. Study the cellular behaviors regulated by En1/2 in developing GNs and DCN projection neurons using conditional genetics and characterizing cellular behaviors in vivo, and in vitro with live imaging. Aim 2. Identify critical target genes o EN1/2 in GN precursors and DCN projection neurons using comparative microarray analysis and ChIP-seq.

描述（由申请人提供）：小脑（Cb）除了在熟练的运动表现中起关键作用外，还涉及认知和社会功能。