Semaphorin-neuropilin regulation of neuronal connectivity

描述（由申请人提供）：神经回路的形成依赖于轴突和树突生长、发育期间的精确引导事件、适当靶细胞的识别以及突触连接的后续形成和细化。每个阶段的表征对于理解调节所有行为的神经元电路的组装至关重要。这些发育过程中的缺陷是与疾病和神经障碍相关的认知障碍的基础。事实上，异常的树突形态和突触与一系列的神经精神疾病，强调需要了解这些事件在电路形成的细胞和分子基础。 这项工作的目的是了解细胞外的线索存在于出生后的大脑控制投射神经元的细胞体位于皮层的V层内的形态发育。我们将阐明这些神经元的形态发育的脑信号蛋白家族的指导线索和它们的神经纤毛蛋白和丛蛋白受体的分泌成员的作用的功能和机制。我们的初步工作表明，semaphorin 3F（Sema 3F）和它的neuropilin-2（Npn-2）受体在体内的功能，支配皮质锥体神经元顶端树突棘的形态和突触发生，而semaphorin 3A（Sema 3A）促进基础树突乔木的制定。因此，结构上相关的线索指示第五层锥体神经元发育的不同步骤，在它们上面形成的突触的位置、形态和数量，以及正常功能的皮层回路的起源。机械上，我们发现，本地化的Npn-2受体仅限于初级顶端树突的过程中，而Npn-1位于基底和顶端树突。此外，Npn-2在突触形成部位-PSD富集。这些发现导致的假设，semaphorin受体定位的基础Sema 3A和Sema 3F的特异性的行动。 我们建议在这里调查神经纤毛蛋白和丛蛋白受体分布的调节，分泌的脑信号蛋白受体信号传导机制，以及这些脑信号蛋白配体的来源和作用方式在出生后皮层神经元发育。由于我们的研究结果将阐明树突形态和突触的空间限制性调节的机制，因此，所提出的目标将开始解决复杂的皮层连接模式是如何产生和维持的。最后，虽然拟议的工作的重点是对初级投射神经元的皮层，第V层锥体神经元的形态和突触的发展，这里所取得的发现将有重要的影响，为确定整个大脑的神经电路组装的分子和细胞基础。 公共卫生相关性：拟议的研究将定义组织哺乳动物皮层中精确和空间限制的神经元连接模式的分子机制。这些发现将为我们目前对大脑中神经元形态和连接如何形成的理解提供新的见解。重要的是，由于异常的神经元形态和突触在皮层与一系列的神经精神疾病，这项工作将告知诊断和治疗策略，以改善这些疾病。

DESCRIPTION (provided by applicant): The formation of neural circuits relies on axonal and dendritic growth, precise guidance events during development, recognition of appropriate target cells, and the subsequent formation and refinement of synaptic connections. Characterization of each of these stages is critical for understanding the assembly of neuron circuits that mediate all behavior. Deficits in these developmental processes underlie cognitive impairments associated with disease and neurologic disorders. Indeed, aberrant dendritic morphologies and synapses are associated with a range of neuropsychiatric disorders, underscoring the need for understanding the cellular and molecular basis of these events during circuit formation. The objective of this work is to understand how extracellular cues present within the postnatal brain control the morphological development of projection neurons whose cell bodies are located within layer V of the cortex. We will elucidate the functions and mechanisms of action of secreted members of the semaphorin protein family of guidance cues and their neuropilin and plexin receptors on the morphological development of these neurons. Our preliminary work shows that semaphorin 3F (Sema3F) and its neuropilin-2 (Npn-2) receptor function in vivo to govern cortical pyramidal neuron apical dendritic spine morphology and synaptogenesis, whereas semaphorin 3A (Sema3A) promotes the elaboration of basal dendritic arbors. Thus, structurally related cues instruct distinct steps in the development of layer V pyramidal neurons, the location, morphology, and number of synapses that form upon them, and hence the genesis of normal functioning cortical circuits. Mechanistically, we found that localization of the Npn-2 receptor is restricted to primary apical dendritic processes, while Npn-1 is located on both basal and apical dendrites. In addition, Npn-2 is enriched at sites of synapse formation-the PSD. These findings lead to the hypothesis that semaphorin receptor localization underlies Sema3A and Sema3F specificity of action. We propose here to investigate the regulation of neuropilin and plexin receptor distribution, secreted semaphorin receptor signaling mechanisms, and the source and mode of action of these semaphorin ligands during postnatal cortical neuron development. Since our findings will shed light on the mechanisms underlying spatially restricted regulation of dendritic morphology and synapses, the proposed Aims will begin to address how complex cortical connectivity patterns are generated and maintained. Finally, while the focus of the proposed work is on the morphologic and synaptic development of the primary projection neuron of the cortex, the layer V pyramidal neuron, the discoveries made here will have important implications for defining the molecular and cellular basis of neural circuit assembly throughout the brain. PUBLIC HEALTH RELEVANCE: The proposed studies will define the molecular mechanisms that organize precise and spatially restricted neuronal connectively patterns in the mammalian cortex. These discoveries will provide new insight into our current understanding of how neuronal morphology and connections are formed in the brain. Importantly, since aberrant neuronal morphology and synapses in the cortex are associated with a range of neuropsychiatric disorders, this work will inform diagnostic and therapeutic strategies for ameliorating these disorders.