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.
