Developmental mechanisms specifying vagal innervation of organ targets

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Project Summary / Abstract: During development, the central nervous system establishes precise connections with the body to coordinate organ function. A crucial component of this communication between the brain and body is the vagus nerve (cranial nerve X), which innervates multiple organ systems including the heart, lungs, and digestive tract to regulate blood pressure, heart rate, respiration, and digestion. Despite this important role, the molecular mechanisms guiding the vagus nerve to these organ targets remain completely unknown. We have developed the zebrafish embryo as a powerful model for interrogating vagus nerve development, taking advantage of its optical clarity and genetic accessibility. The vagus is comprised of both ascending sensory fibers that transmit organ state to the brain, and descending motor projections that deliver reciprocal motor commands to the organs. The vagus nerve also targets pharyngeal arch-derived muscles in the head, and the Moens lab has previously described a topographic relationship between the positions of motor neurons in the brain and their targets in the head, and has discovered a spatio-temporal mechanisms for the development of this map. The preliminary data I present here demonstrates that vagal motor projections to the organs are also organized topographically, where vagal motor neurons innervating different organs (heart, stomach, intestines) are spatially segregated within the hindbrain vagus nucleus. I also observe vagal motor projections reaching the viscera much earlier than their sensory counterparts, leading me to hypothesize that correct motor innervation of the viscera is required for subsequent sensory innervation. Here, I propose to address these hypotheses through the following aims. In Aim 1, I will use genetic tools along with live imaging and single-cell RNA sequencing to determine the molecular mechanisms guiding subsets of vagus motor neurons to the heart and gut. I will identify candidate molecules (transcription factors and cell-surface proteins) determining the topographic organization of somatic innervation and test the role of these candidates using reverse genetics. In Aim 2, I will determine the mechanisms guiding vagal sensory neurons to the appropriate organ targets and test the dependence of sensory innervation on the correct establishment of vagal motor innervation. This work will reveal how a major pathway of communication between the brain and organs is established during development.