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Rac1 and Nectin3 are essential for PCP-directed axon guidance in the peripheral auditory system.

Shaylyn Clancy1, Nicholas Xie1, Tess Eluvathingal Muttikkal1

  • 1Department of Cell Biology, University of Virginia Health System, Charlottesville, VA, 22903, United States.

Biorxiv : the Preprint Server for Biology
|June 19, 2024
PubMed
Summary

Planar Cell Polarity (PCP) pathway regulates spiral ganglion neuron (SGN) development. This study identifies Nectin3 and Rac1 as key downstream effectors controlling SGN axon guidance in the cochlea.

Keywords:
Nectin3Planar Cell PolarityRac1axon guidancehair cellintermediate targetspiral ganglion neuronsupporting cells

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Biology

Background:

  • Spiral ganglion neurons (SGNs) are crucial for hearing, connecting auditory receptors to the brain.
  • Type II SGNs (SGNIIs) innervate outer hair cells and exhibit specific developmental turning behaviors.
  • The Planar Cell Polarity (PCP) pathway is known to influence SGNII afferent turning, but the molecular mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the downstream molecular mechanisms by which the PCP pathway regulates SGNII afferent axon guidance.
  • To identify specific genes and proteins involved in mediating environmental cues for SGNII turning.
  • To understand the role of cochlear supporting cells in SGNII development.

Main Methods:

  • In vivo genetic analysis in mouse models.
  • Investigation of gene localization and protein interactions.
  • Epistasis analysis to determine genetic pathway relationships.

Main Results:

  • The core PCP gene Vangl2 regulates the localization of Rac1 and Nectin3 in cochlear supporting cells.
  • Loss of Rac1 or Nectin3 partially recapitulates SGNII turning defects observed in Vangl2 mutants.
  • Rac1 plays a non-autonomous role in SGNII turning by influencing PCP protein localization.

Conclusions:

  • Nectin3 and Rac1 are novel downstream effectors of the PCP pathway in SGNII axon guidance.
  • These molecules regulate cell adhesion and cytoskeleton dynamics in supporting cells, guiding SGNII afferents.
  • The findings reveal a conserved mechanism for PCP-directed axon pathfinding in the developing cochlea.