Scientific Papers

Development and regeneration of the vagus nerve


Introduction

For centuries, the vagus nerve has been revered as an anatomical wonder for its structural complexity. It extends a multitude of tendrils that reach from the ear to the colon and touch nearly every organ in between. As the most significant component of the parasympathetic nervous system, the vagus nerve is a major sensor of internal organ state and reflexively controls key bodily functions such as swallowing, coughing, speech, vomiting, respiration, blood pressure, heart rate, digestion, metabolism, sweating, and exocrine, endocrine, and hormone secretion [1], [2], as well as being a major mediator of the gut-brain axis [3] and the neuroimmune axis [4]. But from this nerve’s complexity, a paradox emerges. Trace its many tendrils back to their origins, and you’ll find that they emerge from only a few small clusters of neurons. How do these few clusters manage the task of accurately controlling a much larger set of tissues and functions? Recent advances in single-cell transcriptomics have revealed a stunning molecular heterogeneity within these clusters and have begun to unravel the correspondence between a vagus neuron’s molecular identity and its tissue target and functional role, leading to an understanding that the nerve’s multifunctionality arises from the organization of its neurons into topographically and/or molecularly distinct subgroups [5], [6], [7], [8], [9], [10], [11], [12], [13]. The next major milestone in vagus biology will be to discover the mechanisms by which the molecular heterogeneity between vagus neurons is translated to promote the organized construction of the nerve’s complex anatomical and functional circuitry, a challenge which lies squarely in the realm of developmental biology. In this review, we explore the current understanding of the genetic and molecular basis of vagus circuit construction in the contexts of embryonic development and regeneration as revealed in fish, avian, rodent, and human models, and discuss opportunities and challenges for the future of vagus neurodevelopment.



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