Semaphorin-neuropilin regulation of neuronal connectivity

描述(申请人提供)：神经回路的形成依赖于轴突和树突的生长，发育过程中的精确指导事件，适当的靶细胞的识别，以及随后突触连接的形成和完善。这些阶段中的每一个阶段的特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神经精神障碍有关，这突显了在电路形成过程中理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线索如何控制其胞体位于大脑皮层V层的投射神经元的形态发育。我们将阐明引导线索信号素蛋白家族的分泌成员以及它们的神经粘连蛋白和丛连蛋白受体在这些神经元的形态发育中的功能和作用机制。我们的初步工作表明，信号素3F(Sema3F)及其神经粘连蛋白-2(Npn-2)受体在体内调节皮质锥体神经元树突棘顶端的形态和突触发生，而信号素3A(Sema3A)促进基础树突状突起的形成。因此，结构上相关的线索指示了V层锥体神经元发育的不同步骤，以及在其上形成的突触的位置、形态和数量，从而导致正常功能皮质回路的起源。从机制上讲，我们发现Npn-2受体的定位仅限于初级顶树突状突起，而Npn-1则定位于基树突和顶树突上。此外，Npn-2在突触形成的部位--PSD-2也有丰富的表达。这些发现导致了一种假设，即信号素受体的定位是Sema3A和Sema3F动作特异性的基础。我们建议研究神经粘连蛋白和神经丛蛋白受体分布的调节，分泌性信号素受体信号转导机制，以及这些信号素配体在出生后皮质神经元发育过程中的来源和作用方式。由于我们的发现将阐明树突形态和突触的空间受限调控的潜在机制，拟议的目标将开始解决复杂的皮质连接模式是如何产生和维持的。最后，虽然拟议工作的重点是大脑皮层初级投射神经元--V层锥体神经元的形态和突触发育，但这里的发现将对确定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.