Biology subjects

Navarro, M. F.

Publications and source records attributed to Navarro, M. F..

3 recordsLinked to original sources

bioRxiv2026

Huntingtin and Celsr3 Orchestrate Spontaneous Long-Distance Spinal Cord Regeneration

Spontaneous spinal cord regeneration is an endogenous process operational in diverse vertebrate and select mammalian species. Yet despite resulting in functional regeneration, axonal regrowth dynamics as well as underlying molecular programs are largely unknown. Live-cell imaging following laser axotomy of individual zebrafish spinal cord M-cell axons reveals a time-sensitive multistep process. From a genetic screen we uncover previously unrecognized roles for two evolutionary conserved genes, celsr3 and huntingtin (htt) in spontaneous spinal cord regeneration. Specifically, we find that htt is critical to initiate a transcriptional injury response in regenerating M-cells, enabling their axon to traverse the injury site. Once axons cross the injury site celsr3 functions to increase growth rates, while both celsr3 and htt function to sustain long-range axonal growth. Moreover, we show that htt is dispensable for optic nerve and peripheral motor neuron regeneration, and that reducing soma-to-injury site distance in htt mutant M-cell axons partially restores regeneration, demonstrating a selective role in long-range CNS axon regeneration. Consistent with a transport-based mechanism, genetic knockdown of htt-associated axonal transport proteins recapitulates the htt mutant regeneration phenotype. Combined, our results provide compelling evidence for a time and distance-sensitive multistep molecular framework in which celsr3 dependent growth rate modulation and htt dependent axonal transport promote spontaneous, long-range spinal cord regeneration.

neuroscience↗

bioRxiv2024

Celsr3 drives development and connectivity of the acoustic startle hindbrain circuit

In the developing brain, groups of neurons organize into functional circuits that direct diverse behaviors. One such behavior is the evolutionarily conserved acoustic startle response, which in zebrafish is mediated by a well-defined hindbrain circuit. While numerous molecular pathways that guide neurons to their synaptic partners have been identified, it is unclear if and to what extent distinct neuron populations in the startle circuit utilize shared molecular pathways to ensure coordinated development. Here, we show that the planar cell polarity (PCP)-associated atypical cadherins Celsr3 and Celsr2, as well as the Celsr binding partner Frizzled 3a/Fzd3a, are critical for axon guidance of two neuron types that form synapses with each other: the command-like neuron Mauthner cells that drive the acoustic startle escape response, and spiral fiber neurons which provide excitatory input to Mauthner cells. We find that Mauthner axon growth towards synaptic targets is vital for Mauthner survival. We also demonstrate that symmetric spiral fiber input to Mauthner cells is critical for escape direction, which is necessary to respond to directional threats. Moreover, we identify distinct roles for Celsr3 and Celsr2, as Celsr3 is required for startle circuit development while Celsr2 is dispensable, though Celsr2 can partially compensate for loss of Celsr3 in Mauthner cells. This contrasts with facial branchiomotor neuron migration in the hindbrain, which requires Celsr2 while we find that Celsr3 is dispensable. Combined, our data uncover critical and distinct roles for individual PCP components during assembly of the acoustic startle hindbrain circuit. HighlightsO_LIThe PCP cadherin Celsr3 regulates startle circuit development in zebrafish C_LIO_LICelsr3 and other PCP-associated proteins promote Mauthner axon growth and guidance C_LIO_LICelsr3 is required for spiral fiber and glia targeting to the Mauthner axon cap C_LIO_LISymmetric spiral fiber input to Mauthners is critical for escape direction C_LI

neuroscience↗

bioRxiv2021

Agrin/Lrp4 signal constrains MuSK activity during neuromuscular synapse development in appendicular muscle

The receptor tyrosine kinase MuSK, its co-receptor Lrp4 and the Agrin ligand constitute a signaling pathway critical in axial muscle for neuromuscular synapse development, yet whether this pathway functions similarly in appendicular muscle is unclear. Here, using the larval zebrafish pectoral fin, equivalent to tetrapod forelimbs, we show that like axial muscle, developing appendicular muscles develop aneural acetylcholine receptor (AChR) clusters prior to innervation. As motor axons arrive, neural AChR clusters form, eventually leading to functional synapses in a MuSK-dependent manner. Surprisingly, we find that loss of Agrin or Lrp4 function, which abolishes synaptic AChR clusters in axial muscle, results in enlarged presynaptic nerve endings and progressively expanding appendicular AChR clusters, mimicking the consequences of motoneuron ablation. Moreover, musk depletion in lrp4 mutants partially restores synaptic AChR patterning. Combined, our results provide compelling evidence that, in contrast to axial muscle in which Agrin/Lrp4 stimulates MuSK activity, Agrin/Lrp4 signaling in appendicular muscle constrains MuSK activity to organize neuromuscular synapses. Thus, we reveal a previously unappreciated role for Agrin/Lrp4 signaling, thereby highlighting distinct differences between axial and appendicular synapse development.

neuroscience↗