期刊
DEVELOPMENTAL BIOLOGY
卷 326, 期 1, 页码 86-100出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2008.10.033
关键词
Notch; Lateral inhibition; Hair cell; Regeneration; Chicken; Transdifferentiation; Progenitor
资金
- Hearing Regeneration Initiative [NIH DC03696, NIH DC03829, NIH DC04661, NIH HD002274]
- Cancer Research UK
- National Organization of Hearing Research
- Deafness Research UK
- Biotechnology and Biological Sciences Research Council [BB/F007175/1] Funding Source: researchfish
- BBSRC [BB/F007175/1] Funding Source: UKRI
Unlike mammals, birds regenerate auditory hair cells (HCs) after injury. During regeneration, mature nonsensory supporting cells (SCs) leave quiescence and convert into HCs, through non-mitotic or mitotic mechanisms. During embryogenesis, Notch ligands from nascent HCs exert lateral inhibition, restricting HC production. Here, we examined whether Notch signaling (1) is needed in mature birds to maintain the HC/SC pattern in the undamaged auditory epithelium or (2) governs SC behavior once HCs are injured. We show that Notch pathway genes are transcribed in the mature undamaged epithelium, and after HC injury, their transcription is upregulated in the region of highest mitotic activity. In vitro treatment with DAFT, an inhibitor of Notch activity, had no effect on SCs in the undamaged epithelium. Following HC damage, DART had no direct effect on SC division. However, after damage, DAPT caused excessive regeneration of HCs at the expense of SCs, through both mitotic and non-mitotic mechanisms. Conversely, overexpression of activated Notch in SCs after damage caused them to maintain their phenotype and inhibited HC regeneration. Therefore, signaling through Notch is not required for SC quiescence in the healthy epithelium or to initiate HC regeneration after damage. Rather, Notch prevents SCs from regenerating excessive HCs after damage. (C) 2008 Elsevier Inc. All rights reserved.
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