Deciphering Trophic Signaling Programs Governing Peripheral Sensory Nervous System Development

体验凉风或表演复杂的舞步都是通过一个精确的 经过校准的体感神经系统。这种校准是如何在神经系统发育过程中发生的 代表了一个长期存在的问题，这个问题对于理解我们如何感知环境是至关重要的。全 周围神经系统(PNS)中的感觉神经元来自单一的神经沟 在背根神经节中迅速分化为分子上不同类型神经元的前体细胞 (DRG)，每个感觉神经元类别负责检测不同的环境模式。一直以来都是 假设这些神经元被预先编程成为伤害性感受器或本体感受器，然而，我们的 初步实验表明，感觉神经元的最终谱系选择是在遇到 来自目标组织(即皮肤或肌肉)的神经营养因子。 在这个提议中，我们试图定义这些因素如何对驱动细胞的营养信号轴起作用 世系选择。我们将这个信号轴或“营养变阻器”定义为一种可溶性的靶源性神经营养物质。 该因子是同源受体酪氨酸激酶，是一种协同或拮抗的TNFR家族成员。我们的 中心前提是靶点衍生的营养信号类型和/或水平的差异驱动感觉 神经前体细胞朝向至少13个终末细胞命运之一。我们的目标是定义营养变阻器 对这些发展选择中的每一个负责。为了解决这个问题，我们将首先绘制出中的所有单元类型 应用单细胞质量细胞术对发育中的背根节进行每日时间点跨胚胎和 出生后发育以制作三叉神经核发育细胞图谱(Aim1)。确定……的影响 营养信号变阻器对这些细胞类型的分化，我们将研究串扰和 神经营养因子受体下游细胞信号通路与TNFR家族的趋同 体外成员(AIM2)，并测试体内干扰这些信号通路如何影响PNS 发育和感觉行为表型(Aim3)。 为了解决这些研究目标，我们正在开创一种组合方法，利用我们的 在高维单细胞分析、小鼠遗传学和神经营养信号方面的专业知识，以破译 控制三叉神经节细胞分化和发育的营养信号变阻器。我们处于有利地位 勾勒出该领域多年来一直难以捉摸的机制。这项工作将有助于我们理解 感觉神经元的发展，使数百万遭受疼痛和 运动障碍。这项提案中描述的机制将对我们的 对其他形式的理解，包括味觉、听觉、嗅觉和视觉。

Experiencing a cool breeze or performing an intricate dance step are both realized through a precisely calibrated somatosensory nervous system. How this calibration occurs during nervous system development represents a long-standing question that is fundamental to understanding how we sense our environment. All sensory neurons in the peripheral nervous system (PNS) are derived from a single pool of neural crest progenitor cells, which rapidly differentiate into molecularly distinct classes of neurons in the dorsal root ganglia (DRG), each sensory neuron class responsible for detecting distinct environmental modalities. It has long been assumed that these neurons are pre-programmed to become either nociceptor or proprioceptor, however, our preliminary experiments suggest that final lineage choices of sensory neurons are made after encountering neurotrophic factors derived from target tissues (i.e. skin or muscle). In this proposal, we seek to define how such factors contribute to a trophic signaling axis that drives cell lineage choices. We define this signaling axis or “trophic rheostat” as a soluble target-derived neurotrophic factor, it’s cognate receptor tyrosine kinase, and a synergistic or antagonistic TNFR family member. Our central premise is that differences in the type and/or levels of target-derived trophic signaling drive sensory neuron progenitors toward one of at least 13 terminal cell fates. Our goal is to define the trophic rheostats responsible for each of these developmental choices. To address this idea, we will first map out all cell types in the developing DRG by single cell mass cytometry, measuring at daily timepoints across embryonic and postnatal development to produce a developmental cell atlas of the PNS (Aim1). To determine the influence of trophic signaling rheostats on the differentiation of these cell types, we will investigate the cross-talk and convergence of cell signaling pathways downstream of neurotrophic factor receptors and TNFR family members in vitro (Aim2), and test how perturbing these signaling pathways in vivo influences PNS development and sensory behavioral phenotypes (Aim3). To address these research aims, we are pioneering a combinatorial approach that leverages our expertise in high dimensional single cell analysis, mouse genetics, and neurotrophic signaling, to decipher the trophic signaling rheostats that govern cell differentiation and development in the PNS. We are well positioned to delineate mechanisms that have eluded the field for years. This work will inform our understanding of the development of sensory neurons, rationalizing treatments for the millions of individuals suffering from pain and movement disorders. The mechanisms delineated in this proposal will have broad implications for our understanding of other modalities including taste, audition, olfaction, and vision.