title: Otic mesenchyme cells regulate spiral ganglion axon fasciculation through a Pou3f4/EphA4 signaling pathway.
abstract: Peripheral axons from auditory spiral ganglion neurons (SGNs) form an elaborate series of radially and spirally oriented projections that interpret complex aspects of the auditory environment. However, the developmental processes that shape these axon tracts are largely unknown. Radial bundles are comprised of dense SGN fascicles that project through otic mesenchyme to form synapses within the cochlea. Here, we show that radial bundle fasciculation and synapse formation are disrupted when Pou3f4 (DFNX2) is deleted from otic mesenchyme. Further, we demonstrate that Pou3f4 binds to and directly regulates expression of Epha4, Epha4⁻/⁻ mice present similar SGN defects, and exogenous EphA4 promotes SGN fasciculation in the absence of Pou3f4. Finally, Efnb2 deletion in SGNs leads to similar fasciculation defects, suggesting that ephrin-B2/EphA4 interactions are critical during this process. These results indicate a model whereby Pou3f4 in the otic mesenchyme establishes an Eph/ephrin-mediated fasciculation signal that promotes inner radial bundle formation.
authors.affiliation: Laboratory of Cochlear Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA. coatet@nidcd.nih.gov
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coate
authors.forename: Steven
authors.initials: S
authors.lastname: Raft
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhao
authors.forename: Aimee K
authors.initials: AK
authors.lastname: Ryan
authors.forename: E Bryan
authors.initials: EB
authors.lastname: Crenshaw
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kelley
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018920:Coculture Techniques; D004622:Embryo, Mammalian; D036388:Ephrin-B2 / Q000172:deficiency; D005260:Female; D008297:Male; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D050809:POU Domain Factors / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013136:Spiral Ganglion / Q000166:cytology*; D013569:Synapses / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D036388:Ephrin-B2; D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; C074067:Pou3f4 protein, mouse; C486336:Neurog1 protein, mouse