Branched nerve patterning and morphogenesis
In any nerve, guiding growing axons to the correct target tissue(s) is crucial for proper function. In branched nerves, this process presents a particular organizational challenge, as different neurons within the nerve must extend axons along different paths in a highly regulated manner to build the proper innervation pattern. We aim to understand the genetic and cell biological processes that underlie this patterning. Using the conserved zebrafish vagus nerve as a model, we are examining how spatial and temporal heterogeneities in extrinsic signals and intrinsic cell state interact to guide axon target selection within individual neurons, and how individual targeting decisions are coordinated across the tissue to construct large-scale innervation patterns.
Topographic innervation pattern of the branched zebrafish vagus nerve.
Topographic vagus nerve patterning during embryonic development
The vagus motor nerve extends five axon branches which are topographically patterned such that progressively more posterior neurons innervate progressively more posterior targets (illustrated above), making it a perfect model to examine how innervation decisions are regulated to build patterned nerve architectures. We have developed spatial and single-cell genetic, genomic, embryological, and imaging strategies to determine how cells at distinct positions reliably select distinct innervation targets. While topography is classically believed to be controlled by the spatially patterned expression of guidance factors, we found that vagus nerve patterning is instead regulated by temporally patterned signals which specify axon target selection by determining when each neuron generates an axon and establishes innervation competence. This work has revealed several novel cell behaviors by which temporal signals are translated into the patterned initiation, guidance, and termination of vagus axon growth, and we are excited to identify the genetic and cell biological mechanisms that control these processes.
axon branch selection by anterior neurons (left, magenta) in normal (center) or delayed (right) onset of innervation competence
Target-specific vagus regeneration following nerve injury
Tracking single-cell axon regeneration after vagus nerve severing in mosaic animals
While damaged nerves often fail to regenerate in humans, they do so very well in zebrafish. We are using the zebrafish as a model to understand how nerve regeneration is accomplished, with an eye towards improving regenerative therapies in human patients. Misdirected axon growth is a common cause of failed regeneration, but very little is known of how regenerating axons can be guided to the correct targets. To extend our paradigm of examining how single-cell decision making drives innervation patterning to the regeneration context, we have developed tools to manipulate and track single-axon regeneration in a variety of injury contexts. This work has revealed a stunning ability for injured vagus axons to regrow to topographically correct target branches, and we are excited to identify the genetic and cell biological mechanisms that promote this regenerative capacity.
General principles of branched nerve innervation patterning
The vagus nerve is just the beginning. Within the zebrafish (and us!) exist a wealth of branched nerves that exhibit diverse innervation patterns and morphogenetic mechanisms. We are excited to develop new models of branched nerve development and regeneration in order to identify novel patterning mechanisms as well as shared principles of topographic map formation.