N-myc controls proliferation, morphogenesis, and patterning of the inner ear

Elena Domínguez Frutos, Iris López Hernández, Victor Vendrell, Joana Neves, Micaela Gallozzi, Katja Gutsche, Laura Quintana, James Sharpe, Paul S Knoepfler, Robert N. Eisenman, Andreas Trumpp, Fernando Giráldez, Thomas Schimmang

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.

Original languageEnglish (US)
Pages (from-to)7178-7189
Number of pages12
JournalJournal of Neuroscience
Volume31
Issue number19
DOIs
StatePublished - May 11 2011

Fingerprint

Inner Ear
Morphogenesis
Organ of Corti
Cochlea
Ear
Cell Count
Organogenesis
Cyclin-Dependent Kinases
Cyclin D1
Growth
Cell Size
Cell Differentiation
Cell Cycle
Cell Proliferation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Frutos, E. D., Hernández, I. L., Vendrell, V., Neves, J., Gallozzi, M., Gutsche, K., ... Schimmang, T. (2011). N-myc controls proliferation, morphogenesis, and patterning of the inner ear. Journal of Neuroscience, 31(19), 7178-7189. https://doi.org/10.1523/JNEUROSCI.0785-11.2011

N-myc controls proliferation, morphogenesis, and patterning of the inner ear. / Frutos, Elena Domínguez; Hernández, Iris López; Vendrell, Victor; Neves, Joana; Gallozzi, Micaela; Gutsche, Katja; Quintana, Laura; Sharpe, James; Knoepfler, Paul S; Eisenman, Robert N.; Trumpp, Andreas; Giráldez, Fernando; Schimmang, Thomas.

In: Journal of Neuroscience, Vol. 31, No. 19, 11.05.2011, p. 7178-7189.

Research output: Contribution to journalArticle

Frutos, ED, Hernández, IL, Vendrell, V, Neves, J, Gallozzi, M, Gutsche, K, Quintana, L, Sharpe, J, Knoepfler, PS, Eisenman, RN, Trumpp, A, Giráldez, F & Schimmang, T 2011, 'N-myc controls proliferation, morphogenesis, and patterning of the inner ear', Journal of Neuroscience, vol. 31, no. 19, pp. 7178-7189. https://doi.org/10.1523/JNEUROSCI.0785-11.2011
Frutos ED, Hernández IL, Vendrell V, Neves J, Gallozzi M, Gutsche K et al. N-myc controls proliferation, morphogenesis, and patterning of the inner ear. Journal of Neuroscience. 2011 May 11;31(19):7178-7189. https://doi.org/10.1523/JNEUROSCI.0785-11.2011
Frutos, Elena Domínguez ; Hernández, Iris López ; Vendrell, Victor ; Neves, Joana ; Gallozzi, Micaela ; Gutsche, Katja ; Quintana, Laura ; Sharpe, James ; Knoepfler, Paul S ; Eisenman, Robert N. ; Trumpp, Andreas ; Giráldez, Fernando ; Schimmang, Thomas. / N-myc controls proliferation, morphogenesis, and patterning of the inner ear. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 19. pp. 7178-7189.
@article{9a42e95098594c0d827ef6821fbbbc9b,
title = "N-myc controls proliferation, morphogenesis, and patterning of the inner ear",
abstract = "Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The K{\"o}lliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.",
author = "Frutos, {Elena Dom{\'i}nguez} and Hern{\'a}ndez, {Iris L{\'o}pez} and Victor Vendrell and Joana Neves and Micaela Gallozzi and Katja Gutsche and Laura Quintana and James Sharpe and Knoepfler, {Paul S} and Eisenman, {Robert N.} and Andreas Trumpp and Fernando Gir{\'a}ldez and Thomas Schimmang",
year = "2011",
month = "5",
day = "11",
doi = "10.1523/JNEUROSCI.0785-11.2011",
language = "English (US)",
volume = "31",
pages = "7178--7189",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "19",

}

TY - JOUR

T1 - N-myc controls proliferation, morphogenesis, and patterning of the inner ear

AU - Frutos, Elena Domínguez

AU - Hernández, Iris López

AU - Vendrell, Victor

AU - Neves, Joana

AU - Gallozzi, Micaela

AU - Gutsche, Katja

AU - Quintana, Laura

AU - Sharpe, James

AU - Knoepfler, Paul S

AU - Eisenman, Robert N.

AU - Trumpp, Andreas

AU - Giráldez, Fernando

AU - Schimmang, Thomas

PY - 2011/5/11

Y1 - 2011/5/11

N2 - Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.

AB - Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.

UR - http://www.scopus.com/inward/record.url?scp=79956301875&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79956301875&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0785-11.2011

DO - 10.1523/JNEUROSCI.0785-11.2011

M3 - Article

C2 - 21562282

AN - SCOPUS:79956301875

VL - 31

SP - 7178

EP - 7189

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 19

ER -