EGFR signaling is required for regenerative proliferation in the cochlea: conservation in birds and mammals.
Proliferation and transdifferentiaton of supporting cells in the damaged auditory organ of birds lead to robust regeneration of sensory hair cells. In contrast, regeneration of lost auditory hair cells does not occur in deafened mammals, resulting in permanent hearing loss. In spite of this failure of regeneration in mammals, we have previously shown that the perinatal mouse supporting cells harbor a latent potential for cell division. Here we show that in a subset of supporting cells marked by p75, EGFR signaling is required for proliferation, and this requirement is conserved between birds and mammals. Purified p75+ mouse supporting cells express receptors and ligands for the EGF signaling pathway, and their proliferation in culture can be blocked with the EGFR inhibitor AG1478. Similarly, in cultured chicken basilar papillae, supporting cell proliferation in response to hair cell ablation requires EGFR signaling. In addition, we show that EGFR signaling in p75+ mouse supporting cells is required for the down-regulation of the cell cycle inhibitor p27(Kip1) (CDKN1b) to enable cell cycle re-entry. Taken together, our data suggest that a conserved mechanism involving EGFR signaling governs proliferation of auditory supporting cells in birds and mammals and may represent a target for future hair cell regeneration strategies.
Division of Cell Biology and Genetics, House Research Institute, 2100 W 3rd St., Los Angeles, CA 90057, USA.
Patricia M
PM
White
Jennifer S
JS
Stone
Andrew K
AK
Groves
Neil
N
Segil
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002645:Chickens; D002867:Chromones / Q000494:pharmacology; D003051:Cochlea / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000378:metabolism; D007760:Labyrinth Supporting Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D009924:Organ Culture Techniques; D009925:Organ of Corti / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology
D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors; D049452:Green Fluorescent Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D020800:Receptor, Nerve Growth Factor; D020032:Tyrphostins; C493961:Cdkn1b protein, mouse; C101044:RTKI cpd; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one