{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:05:08Z","timestamp":1790244308265,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["BX001205"],"award-info":[{"award-number":["BX001205"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"award":["BX001205"],"award-info":[{"award-number":["BX001205"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Australian National Health and Medical Research Council","award":["APP1089838"],"award-info":[{"award-number":["APP1089838"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"crossref"}]},{"award":["APP1089838"],"award-info":[{"award-number":["APP1089838"]}],"id":[{"id":"https:\/\/ror.org\/011kf5r70","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Spiral ganglion neurons (SGNs) relay auditory information from cochlear sensory cells to the central nervous system (CNS). During development, neurotrophins (NTs) secreted by sensory and supporting cells promote SGN dendrite outgrowth. In injury models, exogenous NTs have been used to stimulate SGN regeneration after damage. Following ligand binding, NT-Trk receptor complexes are internalized and may undergo recycling or degradation, or remain intracellular as \u201csignaling endosomes\u201d that can be retrogradely transported to the soma to influence gene expression, survival, and neuritogenesis. Here, we investigated the role of Trk-containing endosomes in SGNs. Neonatal rat SG explants were treated with BDNF and NT-3 in combination with inhibitors targeting distinct steps of endocytosis. Neurite number and length were quantified and compared to untreated controls. Inhibition of actin polymerization (cytochalasin-B) or dynamin (Dynasore) strongly suppressed neurite outgrowth in both NT-treated and untreated explants. Similarly, inhibitors of clathrin-mediated endocytosis, including those acting upstream of dynamin, reduced neuritogenesis under both conditions. In contrast, inhibition of clathrin-independent pathways diminished neurite growth only in the absence of NTs. Blocking retrograde transport of endosomes to the trans-Golgi network (Retro-2) selectively increased neurite length in NT-treated explants, while inhibition of retrograde transport along neurites (Mycalolide B) markedly reduced both neurite number and extension regardless of NT treatment. These findings suggest that basal SGN neuritogenesis relies on both clathrin-dependent and clathrin-independent endocytosis, whereas NT-induced neurite growth is specifically mediated through clathrin- and dynamin-dependent mechanisms. Although some inhibitors also disrupt actin polymerization, the lack of effect from clathrin-independent inhibitors supports clathrin-mediated internalization as the predominant pathway for NT-driven SGN growth.<\/jats:p>","DOI":"10.3390\/ijms27198527","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:07:54Z","timestamp":1790240874000},"page":"8527","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endocytosis and Endocytic Neurotrophin Signaling in Developing Spiral Ganglion Neurons"],"prefix":"10.3390","volume":"27","author":[{"given":"Shannon","family":"Doolittle","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, University of California San Diego (UCSD), La Jolla, CA 92093, USA"},{"name":"Audiology, Mary Bridge Children\u2019s Hospital, Tacoma, WA 98405, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Kwang","family":"Pak","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, University of California San Diego (UCSD), La Jolla, CA 92093, USA"},{"name":"Research Department, VA San Diego Medical Center, San Diego, CA 92161, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Eduardo","family":"Chavez","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, University of California San Diego (UCSD), La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Gary D.","family":"Housley","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Facility, Department of Physiology, School of Biomedical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5765-9496","authenticated-orcid":false,"given":"Arwa","family":"Kurabi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, University of California San Diego (UCSD), La Jolla, CA 92093, USA"},{"name":"Research Department, VA San Diego Medical Center, San Diego, CA 92161, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"project-administration","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Allen F.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, University of California San Diego (UCSD), La Jolla, CA 92093, USA"},{"name":"Research Department, VA San Diego Medical Center, San Diego, CA 92161, USA"},{"name":"Department of Neurosciences, University of California San Diego (UCSD), La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10162001000086","article-title":"Ras\/MEK but not p38 signaling mediates NT-3-induced neurite extension from spiral ganglion neurons","volume":"2","author":"Aletsee","year":"2001","journal-title":"J. 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