Biology subjects

Mathiaparanam, J.

Publications and source records attributed to Mathiaparanam, J..

4 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↗

bioRxiv2025

Inhibition of Cxcr4 chemokine receptor signaling improves habituation learning and increases cAMP-PKA signaling in a zebrafish model of Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder caused by loss of function mutations in the gene neurofibromin 1 (NF1). NF1 encodes neurofibromin, a multifunctional tumor suppressing protein that regulates Ras, cAMP, and dopamine signaling. NF1 predisposes patients to a wide range of symptoms, including peripheral nerve tumors, brain tumors, and cognitive dysfunction. Despite considerable work using animal models to investigate the role of neurofibromin in behavior, translating research into treatment for NF1-associated cognitive dysfunction has not yet been successful. Here, we identify Cxcr4 chemokine receptor signaling as a regulator of habituation learning and modulator of cAMP-PKA signaling in nf1 mutant larval zebrafish. Combining a small-molecule drug screen and RNAseq analysis, we show that cxcr4b expression is increased in nf1 mutants and that pharmacological inhibition of Cxcr4 with AMD3100 (Plerixafor) improves habituation learning in nf1 mutants. We further demonstrate that Plerixafor treatment activates cAMP-PKA pathway signaling but has limited effects on Ras-Raf-MEK-ERK pathway signaling in the nf1 mutant brain. CXCR4 was previously identified as a potential therapeutic target for neurofibromin-deficient tumorigenesis. Our results provide evidence that Cxcr4 signaling also regulates neurofibromin-dependent cognitive function.

neuroscience↗

bioRxiv2024

Serotonin neuromodulation directs optic nerve regeneration

Optic nerve (ON) regeneration in mammalian systems is limited by an overshadowing dominance of inhibitory factors. This has severely hampered the identification of pro- regenerative pathways. Here, we take advantage of the regenerative capacity of larval zebrafish to identify pathways that promote ON regeneration. From a small molecule screen, we identified modulators of serotonin (5-HT) signaling that inhibit ON regeneration. We find several serotonin type-1 receptor genes are expressed in RGC neurons during regeneration and that inhibiting 5- HT1 receptors or components of the 5-HT pathway selectively impedes ON regeneration. We show that 5-HT1 receptor signaling is dispensable during ON development yet is critical for regenerating axons to emerge from the injury site. Blocking 5-HT receptors once ON axons have crossed the chiasm does not inhibit regeneration, suggesting a selective role for 5-HT receptor signaling early during ON regeneration. Finally, we show that agonist-mediated activation of 5-HT1 receptors leads to enhanced and ectopic axonal regrowth. Combined, our results provide evidence for mechanisms through which serotonin-dependent neuromodulation directs ON regeneration in vivo. Summary Statement5-HT1 receptors selectively promote early optic nerve regrowth in zebrafish but are dispensable during development. Serotonin receptor-dependent modulation instructs regenerating optic nerve axons toward the brain in vivo.

developmental biology↗

bioRxiv2019

Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function

To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function.

cell biology↗