Transcriptional Control of Motor Neuron Identity and Connectivity. - Renewal - 1

描述（由申请人提供）：控制对哺乳动物至关重要的行为（如运动和呼吸）的神经回路依赖于脊髓内运动神经元（MN）与专用的外周和中枢突触靶点组建立选择性连接的能力。信号通路作用沿着背腹轴的神经管已被证明，以确定早期身份的MN和区分这类从其他神经元类型的脊髓。MN的后续多样化取决于大约20个Hox转录因子的作用，这些转录因子似乎在MN分化的不同阶段是必需的。虽然Hox基因是MN命运特化所必需的，但其活性的靶点尚不清楚，也不了解它们如何实现MN特异性，因为它们在沿着吻尾轴形成图案中具有相对广泛的作用。此外，决定MN中Hox蛋白表达模式的因素还不清楚。在aim1中，我们将描述Hox蛋白的直接靶点，评估它们如何在运动列中受到调节，并确定它们是否以及如何与MN特异性基因程序相交。在aim2中，我们将剖析Hox蛋白特异性控制MN身份方面的机制，重点是Hoxc9蛋白，MN柱状组织的中心决定因素。在aim3中，我们将检验这样的假设，即Hox依赖性MN亚型的组织依赖于Polycomb蛋白的分级活性，以确保适当的有丝分裂后Hox表达模式。这些研究将为Hox蛋白影响MN分化的机制提供基本的见解，并应允许设计从未分化细胞产生MN亚型的策略。

DESCRIPTION (provided by applicant): The neural circuits that govern behaviors vital to mammals, such as locomotion and respiration, rely on the ability of motor neurons (MNs) within the spinal cord to establish selective connections with dedicated sets of peripheral and central synaptic targets. Signaling pathways acting along the dorsoventral axis of the neural tube have been shown to determine the early identity of MNs and distinguish this class from other neuronal types within the spinal cord. The subsequent diversification of MNs depends on the actions of approximately 20 Hox transcription factors, which appear to be required at distinct phases of MN differentiation. While Hox genes are essential for MN fate specification, the targets of their activities are not known, nor is it understood how they achieve MN-specificity, given their relatively broad roles in patterning along the rostrocaudal axis. Moreover the factors that determine the expression patterns of Hox proteins in MNs are poorly defined. In aim1 we will characterize the direct targets of Hox proteins, assess how they are regulated in motor columns, and determine if and how they intersect with MN-specific gene programs. In aim2 we will dissect the mechanisms of Hox protein specificity in controlling facets of MN identity, focusing on the Hoxc9 protein, a central determinant of MN columnar organization. In aim3 we will test the hypothesis that the organization of Hox-dependent MN subtype relies on graded activities of Polycomb proteins that ensure proper postmitotic Hox expression patterns. These studies will provide basic insights into the mechanisms through which Hox proteins influence MN differentiation, and should allow for the design of strategies to generate MN subtypes from undifferentiated cells.