TY - JOUR
T1 - Bone morphogenetic protein 4 antagonizes hair cell regeneration in the avian auditory epithelium
AU - Lewis, Rebecca M.
AU - Keller, Jesse J.
AU - Wan, Liangcai
AU - Stone, Jennifer S.
N1 - Funding Information:
The authors thank Edwin Rubel, Julie Arenberg, and Richard Folsom for helpful discussions throughout the duration of the study. The authors extend their thanks and gratitude to Jialin Shang, Robin Gibson, and Irmina Haq for assistance with experiments. We also thank Glen MacDonald and Brandon Warren for help with digital imaging and data storage. We are grateful to David Raible, Lavinia Sheets, and Kirupa Suthakar for helpful comments prior to manuscript submission. This study was supported by the National Institutes of Health (F30 grant DC012228 , RML; P30 grant DC04661 , Edwin Rubel, PI; and R01 grant DC03696 , JSS), the American Academy of Audiology Foundation (RML); the Howard Hughes Medical Institute (JJK); the Whitcraft Family (JSS); and the Hearing Restoration Project/Hearing Health Foundation (JSS).
Publisher Copyright:
© 2018 Elsevier B.V.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/7
Y1 - 2018/7
N2 - Permanent hearing loss is often a result of damage to cochlear hair cells, which mammals are unable to regenerate. Non-mammalian vertebrates such as birds replace damaged hair cells and restore hearing function, but mechanisms controlling regeneration are not understood. The secreted protein bone morphogenetic protein 4 (BMP4) regulates inner ear morphogenesis and hair cell development. To investigate mechanisms controlling hair cell regeneration in birds, we examined expression and function of BMP4 in the auditory epithelia (basilar papillae) of chickens of either sex after hair cell destruction by ototoxic antibiotics. In mature basilar papillae, BMP4 mRNA is highly expressed in hair cells, but not in hair cell progenitors (supporting cells). Supporting cells transcribe genes encoding receptors for BMP4 (BMPR1A, BMPR1B, and BMPR2) and effectors of BMP4 signaling (ID transcription factors). Following hair cell destruction, BMP4 transcripts are lost from the sensory epithelium. Using organotypic cultures, we demonstrate that treatments with BMP4 during hair cell destruction prevent supporting cells from upregulating expression of the pro-hair cell transcription factor ATOH1, entering the cell cycle, and fully transdifferentiating into hair cells, but they do not induce cell death. By contrast, noggin, a BMP4 inhibitor, increases numbers of regenerated hair cells. These findings demonstrate that BMP4 antagonizes hair cell regeneration in the chicken basilar papilla, at least in part by preventing accumulation of ATOH1 in hair cell precursors.
AB - Permanent hearing loss is often a result of damage to cochlear hair cells, which mammals are unable to regenerate. Non-mammalian vertebrates such as birds replace damaged hair cells and restore hearing function, but mechanisms controlling regeneration are not understood. The secreted protein bone morphogenetic protein 4 (BMP4) regulates inner ear morphogenesis and hair cell development. To investigate mechanisms controlling hair cell regeneration in birds, we examined expression and function of BMP4 in the auditory epithelia (basilar papillae) of chickens of either sex after hair cell destruction by ototoxic antibiotics. In mature basilar papillae, BMP4 mRNA is highly expressed in hair cells, but not in hair cell progenitors (supporting cells). Supporting cells transcribe genes encoding receptors for BMP4 (BMPR1A, BMPR1B, and BMPR2) and effectors of BMP4 signaling (ID transcription factors). Following hair cell destruction, BMP4 transcripts are lost from the sensory epithelium. Using organotypic cultures, we demonstrate that treatments with BMP4 during hair cell destruction prevent supporting cells from upregulating expression of the pro-hair cell transcription factor ATOH1, entering the cell cycle, and fully transdifferentiating into hair cells, but they do not induce cell death. By contrast, noggin, a BMP4 inhibitor, increases numbers of regenerated hair cells. These findings demonstrate that BMP4 antagonizes hair cell regeneration in the chicken basilar papilla, at least in part by preventing accumulation of ATOH1 in hair cell precursors.
KW - ATOH1
KW - BMP4
KW - Hair cell
KW - Regeneration
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U2 - 10.1016/j.heares.2018.04.008
DO - 10.1016/j.heares.2018.04.008
M3 - Article
C2 - 29754876
AN - SCOPUS:85046786252
VL - 364
SP - 1
EP - 11
JO - Hearing Research
JF - Hearing Research
SN - 0378-5955
ER -