The inhibition of cyclin-dependent kinases induces differentiation of supernumerary hair cells and Deiters' cells in the developing organ of Corti.
In the embryonic day 19 organs of Corti, we showed that roscovitine, a chemical inhibitor of cyclin-dependent kinases (CDKs), significantly increased the number of hair cells (HCs) and corresponding supporting cells (SCs) by triggering differentiation of precursor cells without interacting with cell proliferation. The effect of roscovitine was mimicked by other CDK1, 2, 5, and 7 inhibitors but not by CDK4/6 and mitogen-activated protein kinase pathway antagonists. Immunohistochemical analysis indicated that roscovitine-specific intracellular targets, CDK1, 2, 5, and 7, were expressed in the organ of Corti and especially in Hensen's cells. Affinity chromatography studies showed a tight correlation between the protein levels of CDK1/2 and 5 and the rate of roscovitine-induced supernumerary cells in the organ of Corti. In addition, we demonstrated that basal CDK activity was higher and more roscovitine-sensitive at developmental stages that are selectively permissive for the emergence of supernumerary cells. These results suggest that CDKs are involved in the normal development of the organ of Corti and that, at least in E19 embryos, inhibition of CDKs is sufficient to trigger the differentiation of HCs and corresponding SCs, presumably from the Hensen's cell progenitors and/or from progenitors located in the greater epithelial ridge area.
Malgrange
Brigitte
B
Center for Cellular and Molecular Neurobiology, University of Liège, 17 Place Delcour, B-4020 Liège, Belgium. bmalgrange@ulg.ac.be
Knockaert
Marie
M
Belachew
Shibeshih
S
Nguyen
Laurent
L
Moonen
Gustave
G
Meijer
Laurent
L
Lefebvre
Philippe P
PP
D000818:Animals; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors; D002454:Cell Differentiation; D002455:Cell Division; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006198:Hair Cells, Auditory / Q000166:cytology / Q000196:embryology* / Q000201:enzymology; D015151:Immunoblotting; D007150:Immunohistochemistry; D008954:Models, Biological; D009925:Organ of Corti / Q000166:cytology* / Q000196:embryology* / Q000201:enzymology / Q000254:growth & development; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000077546:Roscovitine
D004791:Enzyme Inhibitors; D011687:Purines; D000077546:Roscovitine; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases