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.
Here we seek to understand how sensory perception is calibrated during development. Understanding the pathways governing the peripheral sensory nervous system?s appropriate assembly will inform our treatment strategies for the millions of individuals suffering from pain and movement disorders.
