Transcriptional regulation of neuronal identity and connectivity

神经元身份和连接的转录调控

• 批准号: 8163606
• 负责人: Bin Chen
• 金额: $ 37.15万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8163606
• 关键词: Amyotrophic Lateral Sclerosis; Applications Grants; Autistic Disorder; Axon; Biological; Brain; Brain Diseases; Brain region; Cells; Cerebral cortex; Cognitive; Complex; Data; Development; Developmental Biology; Disease; Epilepsy; Functional disorder; Generations; Genes; Genetic; Goals; Hereditary Disease; Human; Knowledge; Maps; Mediating; Mental Retardation; Midbrain structure; Mining; Molecular; Molecular Biology; Motor; Motor Neurons; Mus; Neurologic; Neurons; Outcome; Pathway interactions; Prevention approach; Process; Research; Schizophrenia; Sensory; Sensory Process; Spinal Cord; Spinal cord injury; Stem cells; Techniques; Testing; Thalamic structure; Transcriptional Regulation; Vent; Work; base; central nervous system injury; design; hindbrain; human disease; information processing; innovation; insight; nervous system disorder; prevent; progenitor; research study; stem cell biology; transcription factor

DESCRIPTION (provided by applicant): The cerebral cortex is the seat for our highest cognitive and perceptual functions. Its function depends on the precise generation of different neuronal subtypes, and proper wiring of the neurons both within the cerebral cortex and between the cortex and other brain regions. Corticothalamic projection neurons extend axons into the thalamus. They are important in sensory processing, and their dysfunction has been implicated in epilepsy. Subcerebral projection neurons project axons into the midbrain, hindbrain, and spinal cord. These neurons are clinically important since they degenerate in Amyotrophic Lateral Sclerosis (ALS) and other diseases, and are damaged in spinal cord injury. Despite their functional importance and extensive involvement in neurological diseases, the molecular mechanisms regulating the generation of these neurons remain largely unknown. It was only recently discovered that Fezf2 regulates the identity and connectivity of subcerebral neurons. However, the underlying mechanism for Fezf2 function has not been determined. In addition, gene(s) regulating corticothalamic neuron identity remain undefined. Lack of such knowledge hinders our effort to understand the biological causes of various developmental and cognitive brain disorders such as ALS, spinal cord injury, mental retardation, schizophrenia, and autism, and prevents us from designing effective strategies to prevent and treat these diseases. In this grant application, we propose to determine the mechanism how the subtype identities and connectivities for subcerebral neurons (aim 1) and corticothalamic neurons (aim 2) are established during development. We will combine mouse genetics, molecular biology and neuroanatomical techniques to achieve these aims. In aim 3, we aim to understand the lineage relationship among different neuronal subtypes in the cerebral cortex using genetic fate mapping experiments. PUBLIC HEALTH RELEVANCE: The proposed research will not only provide deep insight into the mechanisms of human brain development and plasticity, but also will reveal the biological causes of various developmental and cognitive brain disorders such as ALS, spinal cord injury, mental retardation, schizophrenia, and autism. Thus results from the proposed studies will have fundamental importance in developmental biology, stem cell biology, human disease mechanisms and potential therapies.

描述（由申请人提供）：大脑皮层是我们最高认知和感知功能的所在地。它的功能取决于不同神经元亚型的精确生成，以及大脑皮层内以及皮层与其他大脑区域之间的神经元的正确布线。皮质丘脑投射神经元将轴突延伸到丘脑中。它们在感觉处理中很重要，它们的功能障碍与癫痫有关。脑下投射神经元将轴突投射到中脑、后脑和脊髓中。这些神经元在临床上是重要的，因为它们在肌萎缩性侧索硬化症（ALS）和其他疾病中退化，并且在脊髓损伤中受损。尽管它们在神经系统疾病中的功能重要性和广泛参与，但调节这些神经元产生的分子机制在很大程度上仍然未知。直到最近才发现Fezf2调节大脑下神经元的身份和连接。然而，Fezf 2功能的潜在机制尚未确定。此外，调节皮质丘脑神经元身份的基因仍然不确定。缺乏这样的知识阻碍了我们努力了解各种发育和认知大脑疾病的生物学原因，如ALS，脊髓损伤，精神发育迟滞，精神分裂症和自闭症，并阻止我们设计有效的策略来预防和治疗这些疾病。在这个基金申请中，我们建议确定大脑下神经元（目标1）和皮质丘脑神经元（目标2）的亚型身份和连通性是如何在发育过程中建立的机制。我们将结合联合收割机小鼠遗传学、分子生物学和神经解剖学技术来实现这些目标。在目标3中，我们的目标是通过基因命运定位实验来了解大脑皮层不同神经元亚型之间的谱系关系。 公共卫生相关性：这项拟议中的研究不仅将深入了解人类大脑发育和可塑性的机制，还将揭示各种发育和认知大脑障碍的生物学原因，如ALS，脊髓损伤，精神发育迟滞，精神分裂症和自闭症。因此，从拟议的研究结果将在发育生物学，干细胞生物学，人类疾病机制和潜在的治疗方法具有根本的重要性。