Helios is a key transcriptional regulator of outer hair cell maturation

Lauren Chessum; Maggie S. Matern; Michael C. Kelly; Stuart L. Johnson; Yoko Ogawa; Beatrice Milon; Mark McMurray; Elizabeth C. Driver; Andrew Parker; Yang Song; Gemma Codner; Christopher T. Esapa; Jack Prescott; Graham Trent; Sara Wells; Abigail K. Dragich; Gregory I. Frolenkov; Matthew W. Kelley; Walter Marcotti; Steve D.M. Brown; Ran Elkon; Michael R. Bowl; Ronna Hertzano

doi:10.1038/s41586-018-0728-4

Helios is a key transcriptional regulator of outer hair cell maturation

Lauren Chessum
, Maggie S. Matern
, Michael C. Kelly
, Stuart L. Johnson
, Yoko Ogawa
, Beatrice Milon
, Mark McMurray
, Elizabeth C. Driver
, Andrew Parker
, Yang Song
, Gemma Codner
, Christopher T. Esapa
, Jack Prescott
, Graham Trent
, Sara Wells
, Abigail K. Dragich
, Gregory I. Frolenkov
, Matthew W. Kelley
, Walter Marcotti
, Steve D.M. Brown

Ran Elkon, Michael R. Bowl, Ronna Hertzano

Producción científica: Article › revisión exhaustiva

95 Citas (Scopus)

Resumen

The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning¹. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2^cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.

Idioma original	English
Páginas (desde-hasta)	696-724
Número de páginas	29
Publicación	Nature
Volumen	563
N.º	7733
DOI	https://doi.org/10.1038/s41586-018-0728-4
Estado	Published - 2018

Nota bibliográfica

Publisher Copyright:
© 2018 Springer Nature Limited. All rights reserved.

Financiación

Acknowledgements We thank L. Vizor, J. Sanderson and W. Chien for technical help and Z. Ahmed for comments on the manuscript. This work was supported by Action on Hearing Loss (G65 to M.R.B., R.H., W.M. and S.D.M.B.), Medical Research Council (MC_U142684175 to S.D.M.B.), Wellcome Trust (102892 to W.M.), NIDCD/NIH R01DC013817 and R01DC03544 (R.H.), DOD CDMRP MR130240 (R.H.), NIDCD/NIH T32DC00046 and F31DC016218 (M.S.M.), the Intramural Program at NIDCD DC000059 (M.W.K.), and NIDCD/NIH R01DC014658 (G.I.F.). S.L.J. is a Royal Society University Research Fellow. R.E. is a Faculty Fellow of the Edmond J. Safra Center for Bioinformatics at Tel Aviv University. We thank L. Vizor, J. Sanderson and W. Chien for technical help and Z. Ahmed for comments on the manuscript. This work was supported by Action on Hearing Loss (G65 to M.R.B., R.H., W.M. and S.D.M.B.), Medical Research Council (MC_U142684175 to S.D.M.B.), Wellcome Trust (102892 to W.M.), NIDCD/NIH R01DC013817 and R01DC03544 (R.H.), DOD CDMRP MR130240 (R.H.), NIDCD/NIH T32DC00046 and F31DC016218 (M.S.M.), the Intramural Program at NIDCD DC000059 (M.W.K.), and NIDCD/NIH R01DC014658 (G.I.F.). S.L.J. is a Royal Society University Research Fellow. R.E. is a Faculty Fellow of the Edmond J. Safra Center for Bioinformatics at Tel Aviv University.

Financiadores	Número del financiador
Action on Hearing Loss
National Institutes of Health (NIH)
Tel Aviv University
National Institute on Deafness and Other Communication Disorders	R01DC003544, ZIADC000059, T32DC000046, R01DC013817, R01DC014658, F31DC016218
UK Medical Research Council, Engineering and Physical Sciences Research Council	MC_UP_1502/1, MC_U142684175
UK Industrial Decarbonization Research and Innovation Centre	MC_U142684175
DOD CDMRP	DC000059, MR130240, R01DC014658, T32DC00046, F31DC016218
Wellcome Trust	102892

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Chessum, L., Matern, M. S., Kelly, M. C., Johnson, S. L., Ogawa, Y., Milon, B., McMurray, M., Driver, E. C., Parker, A., Song, Y., Codner, G., Esapa, C. T., Prescott, J., Trent, G., Wells, S., Dragich, A. K., Frolenkov, G. I., Kelley, M. W., Marcotti, W., ... Hertzano, R. (2018). Helios is a key transcriptional regulator of outer hair cell maturation. Nature, 563(7733), 696-724. https://doi.org/10.1038/s41586-018-0728-4

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title = "Helios is a key transcriptional regulator of outer hair cell maturation",

abstract = "The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.",

author = "Lauren Chessum and Matern, \{Maggie S.\} and Kelly, \{Michael C.\} and Johnson, \{Stuart L.\} and Yoko Ogawa and Beatrice Milon and Mark McMurray and Driver, \{Elizabeth C.\} and Andrew Parker and Yang Song and Gemma Codner and Esapa, \{Christopher T.\} and Jack Prescott and Graham Trent and Sara Wells and Dragich, \{Abigail K.\} and Frolenkov, \{Gregory I.\} and Kelley, \{Matthew W.\} and Walter Marcotti and Brown, \{Steve D.M.\} and Ran Elkon and Bowl, \{Michael R.\} and Ronna Hertzano",

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doi = "10.1038/s41586-018-0728-4",

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Chessum, L, Matern, MS, Kelly, MC, Johnson, SL, Ogawa, Y, Milon, B, McMurray, M, Driver, EC, Parker, A, Song, Y, Codner, G, Esapa, CT, Prescott, J, Trent, G, Wells, S, Dragich, AK, Frolenkov, GI, Kelley, MW, Marcotti, W, Brown, SDM, Elkon, R, Bowl, MR & Hertzano, R 2018, 'Helios is a key transcriptional regulator of outer hair cell maturation', Nature, vol. 563, n.º 7733, pp. 696-724. https://doi.org/10.1038/s41586-018-0728-4

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AU - Chessum, Lauren

AU - Matern, Maggie S.

AU - Kelly, Michael C.

AU - Johnson, Stuart L.

AU - Ogawa, Yoko

AU - Milon, Beatrice

AU - McMurray, Mark

AU - Driver, Elizabeth C.

AU - Parker, Andrew

AU - Song, Yang

AU - Codner, Gemma

AU - Esapa, Christopher T.

AU - Prescott, Jack

AU - Trent, Graham

AU - Wells, Sara

AU - Dragich, Abigail K.

AU - Frolenkov, Gregory I.

AU - Kelley, Matthew W.

AU - Marcotti, Walter

AU - Brown, Steve D.M.

AU - Elkon, Ran

AU - Bowl, Michael R.

AU - Hertzano, Ronna

PY - 2018

Y1 - 2018

N2 - The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.

AB - The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.

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DO - 10.1038/s41586-018-0728-4

M3 - Article

C2 - 30464345

AN - SCOPUS:85057527127

SN - 0028-0836

VL - 563

SP - 696

EP - 724

JO - Nature

JF - Nature

IS - 7733

ER -

Helios is a key transcriptional regulator of outer hair cell maturation

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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