Survival of adult spiral ganglion neurons requires erbB receptor signaling in the inner ear.
Degeneration of cochlear sensory neurons is an important cause of hearing loss, but the mechanisms that maintain the survival of adult cochlear sensory neurons are not clearly defined. We now provide evidence implicating the neuregulin (NRG)-erbB receptor signaling pathway in this process. We found that NRG1 is expressed by spiral ganglion neurons (SGNs), whereas erbB2 and erbB3 are expressed by supporting cells of the organ of Corti, suggesting that these molecules mediate interactions between these cells. Transgenic mice in which erbB signaling in adult supporting cells is disrupted by expression of a dominant-negative erbB receptor show severe hearing loss and 80% postnatal loss of type-I SGNs without concomitant loss of the sensory cells that they contact. Quantitative RT-PCR analysis of neurotrophic factor expression shows a specific downregulation in expression of neurotrophin-3 (NT3) in the transgenic cochleas before the onset of neuronal death. Because NT3 is critical for survival of type I SGNs during development, these results suggest that it plays similar roles in the adult. Together, the data indicate that adult cochlear supporting cells provide critical trophic support to the neurons, that survival of postnatal cochlear sensory neurons depends on reciprocal interactions between neurons and supporting cells, and that these interactions are mediated by NRG and neurotrophins.
Division of Neuroscience, Children's Hospital, Boston, Massachusetts 02115, USA.
Konstantina
K
Stankovic
Carlos
C
Rio
Anping
A
Xia
Mitsuru
M
Sugawara
Joe C
JC
Adams
M Charles
MC
Liberman
Gabriel
G
Corfas
D000818:Animals; D002470:Cell Survival; D003051:Cochlea / Q000254:growth & development / Q000294:innervation* / Q000378:metabolism; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006198:Hair Cells, Auditory / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D034381:Hearing Loss / Q000209:etiology / Q000473:pathology; D007760:Labyrinth Supporting Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020890:Neuregulin-1; D009475:Neurons, Afferent / Q000166:cytology / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D013136:Spiral Ganglion / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D020933:Neurotrophin 3; C490581:Nrg1 protein, mouse; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4