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的生长，发育过程中的精确引导事件，对适当靶细胞的识别，以及随后突触连接的形成和完善。每个阶段的特征对于理解调节所有行为的神经元回路的组装是至关重要的。这些发育过程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神经精神疾病有关，这强调了在电路形成过程中了解这些事件的细胞和分子基础的必要性。这项工作的目的是了解出生后大脑中存在的细胞外信号如何控制投射神经元的形态发育，其细胞体位于皮层的V层。我们将阐明信号蛋白家族的分泌成员及其神经鞘和丛蛋白受体在这些神经元形态发育中的功能和作用机制。我们的初步研究表明，信号蛋白3F （Sema3F）及其神经匹林-2 （Npn-2）受体在体内控制皮层锥体神经元顶端树突棘的形态和突触发生，而信号蛋白3A （Sema3A）促进基部树突乔木的形成。因此，结构上相关的线索指导了V层锥体神经元发育的不同步骤，在其上形成的突触的位置、形态和数量，从而指导了正常功能皮层回路的形成。在机制上，我们发现Npn-2受体的定位局限于初级根尖树突，而Npn-1受体既位于基部树突，也位于根尖树突。此外，Npn-2在突触形成位点PSD富集。这些发现导致了信号蛋白受体定位是Sema3A和Sema3F特异性作用的基础。本研究旨在探讨神经匹林和丛蛋白受体分布的调控，分泌信号素受体的信号机制，以及这些信号素配体在出生后皮层神经元发育过程中的来源和作用方式。由于我们的发现将揭示树突形态和突触的空间限制调节的机制，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，虽然这项工作的重点是皮层的初级投射神经元，即V层锥体神经元的形态学和突触发育，但这里的发现将对定义整个大脑神经回路组装的分子和细胞基础具有重要意义。

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.