5-245G Moos Tower
515 Delaware St SE
Minneapolis, MN 55455
5-147 Moos Tower
515 Delaware St SE
Minneapolis, MN 55455
Using zebrafish branched nerves as a model, we employ genetic, genomic, embryological and live imaging approaches to understand how single-cell decision-making is regulated and coordinated to generate large-scale patterns of innervation in the nervous system. We take a dual approach to examine how axon target selection is controlled to 1) build patterned branched nerve structures during embryonic development, and 2) rebuild and repattern these structures during regeneration.
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 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, 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.
Target-specific vagus regeneration following nerve injury:
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.
Isabella, A.J., Stonick, J.A., Dubrulle, J., Moens, C.B. (2021). Intrinsic positional memory guides target- specific axon regeneration in the zebrafish vagus nerve. Development 148, dev.199706.
Isabella, A.J., Barsh, G.R., Stonick, J.A., Dubrulle, J., Moens, C.B. (2020). Retinoic Acid organizes the vagus motor topographic map via spatiotemporal coordination of Hgf/Met Signaling. Developmental Cell 53, 344-357.
Barsh, G.R., Isabella, A.J., Moens, C.B. (2017). Vagus motor neuron topographic map determined by parallel mechanisms of hox5 expression and time of axon initiation. Current Biology 27, 3812-3825.
Isabella, A.J. & Horne-Badovinac, S. (2016). Rab10-mediated secretion synergizes with tissue movement to build a polarized basement membrane architecture for organ morphogenesis. Developmental Cell 38, 47-60.
Isabella, A.J. & Horne-Badovinac, S. (2015). Dynamic regulation of basement membrane protein levels promotes egg chamber elongation in Drosophila. Developmental Biology 406, 212-221.
Education and background
- Pathways to Independence K99/R00, National Institute of Neurological Disorders and Stroke, 2021-2026
- Postdoctoral Fellow, Fred Hutchinson Cancer Center
- Ph.D. Developmental Biology, The University of Chicago, 2016
- B.A. Biology, Colorado College, 2009