# Molecular genetic mechanisms of spontaneous spinal cord regeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $432,356

## Abstract

ABSTRACT
In mammals, spinal cord injury frequently leads to irreversible damage mainly due to the very limited capacity of
injured central nervous system (CNS) axons to reconnect with their preinjury targets. Functional regeneration
requires injured CNS axons to extend over long distances and reconnect with their original synaptic targets,
however even in animal models current treatment strategies produce only modest levels of recovery. Despite
enormous progress over the past decades, our knowledge and understanding of the fundamental molecular
pathways and mechanisms that contribute to the process of spinal cord regeneration has left many fundamental
questions unanswered. For example, are growth rates of regenerating axons uniform, are they preprogramed
and invariable or are they modulated as they extend towards and into the injury site? And if so, what mechanisms
and genes regulate and tune regenerating growth rates? In contrast to mammals, non-mammalian vertebrates
including zebrafish have retained a remarkable capacity for spontaneous CNS regeneration. We have developed
a laser-based axotomy approach to study spinal cord regeneration in larval zebrafish at single axon resolution
in otherwise intact animals. From a candidate screen we identified the Cadherin EGF LAG receptor celsr3 to
play a critical role in CNS regeneration. Our preliminary data reveal that in wild type animals regenerating M-ell
axons switch to 3 fold higher growth rates once they cross the injury site. Celsr3 mutant M-cell axons respond
to injury and grow across the injury site at growth rates indistinguishable from wildtype siblings, but then fail to
increase their growth rates and frequently stall prematurely at about 25% of pre-injury length. Thus, our
preliminary results identified a genetic entry point into the fundamental yet understudied question of whether and
if so through which molecular mechanisms regenerating spinal cord axons regulate their growth rates along their
regenerative path as their environment changes. Finally, we find that Celsr3 is also required for optic nerve
regeneration but is dispensable for peripheral nerve regeneration, strongly suggesting that Celsr3 plays a
selective role in CNS axon regeneration. The experiments in this proposal will (1) determine cellular and
molecular mechanism by which Celsr3 growth rates selectively of regenerating CNS axons; (2) identify the
molecular signaling cascade through which celsr3 promotes regeneration; and (3) Identify additional entry points
into pathways that promote spontaneous spinal cord regeneration. Combined, our results are expected to make
significant contributions to fundamental mechanisms that promote spontaneous spinal cord regeneration in vivo,
and lay the foundation for a comprehensive analysis of spontaneous spinal cord regeneration. Although
spontaneous spinal cord regeneration is largely absent in mammals, mechanisms of spontaneous spinal cord
regeneration might be masked and thus undetectab...

## Key facts

- **NIH application ID:** 10783080
- **Project number:** 5R01NS097914-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Granato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $432,356
- **Award type:** 5
- **Project period:** 2016-07-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783080

## Citation

> US National Institutes of Health, RePORTER application 10783080, Molecular genetic mechanisms of spontaneous spinal cord regeneration (5R01NS097914-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10783080. Licensed CC0.

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