N-myc regulates growth and fiber cell differentiation in lens development

Gabriel R. Cavalheiro, Gabriel E. Matos-Rodrigues, Yilin Zhao, Anielle L. Gomes, Deepti Anand, Danilo Predes, Silmara de Lima, Jose G. Abreu, Deyou Zheng, Salil A. Lachke, Ales Cvekl, Rodrigo A.P. Martins

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Myc proto-oncogenes regulate diverse cellular processes during development, but their roles during morphogenesis of specific tissues are not fully understood. We found that c-myc regulates cell proliferation in mouse lens development and previous genome-wide studies suggested functional roles for N-myc in developing lens. Here, we examined the role of N-myc in mouse lens development. Genetic inactivation of N-myc in the surface ectoderm or lens vesicle impaired eye and lens growth, while “late” inactivation in lens fibers had no effect. Unexpectedly, defective growth of N-myc-deficient lenses was not associated with alterations in lens progenitor cell proliferation or survival. Notably, N-myc-deficient lens exhibited a delay in degradation of DNA in terminally differentiating lens fiber cells. RNA-sequencing analysis of N-myc-deficient lenses identified a cohort of down-regulated genes associated with fiber cell differentiation that included DNaseIIβ. Further, an integrated analysis of differentially expressed genes in N-myc-deficient lens using normal lens expression patterns of iSyTE, N-myc-binding motif analysis and molecular interaction data from the String database led to the derivation of an N-myc-based gene regulatory network in the lens. Finally, analysis of N-myc and c-myc double-deficient lens demonstrated that these Myc genes cooperate to drive lens growth prior to lens vesicle stage. Together, these findings provide evidence for exclusive and cooperative functions of Myc transcription factors in mouse lens development and identify novel mechanisms by which N-myc regulates cell differentiation during eye morphogenesis.

Original languageEnglish (US)
Pages (from-to)105-117
Number of pages13
JournalDevelopmental Biology
Volume429
Issue number1
DOIs
StatePublished - Sep 1 2017

Fingerprint

Lenses
Cell Differentiation
Growth
myc Genes
Morphogenesis
Cell Proliferation
RNA Sequence Analysis
Crystalline Lens
Ectoderm
Proto-Oncogenes
Gene Regulatory Networks
Cell Survival
Transcription Factors
Stem Cells

Keywords

  • Cell cycle
  • Denucleation
  • Eye
  • Oncogene
  • Organogenesis
  • Transcription factor

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Cavalheiro, G. R., Matos-Rodrigues, G. E., Zhao, Y., Gomes, A. L., Anand, D., Predes, D., ... Martins, R. A. P. (2017). N-myc regulates growth and fiber cell differentiation in lens development. Developmental Biology, 429(1), 105-117. https://doi.org/10.1016/j.ydbio.2017.07.002

N-myc regulates growth and fiber cell differentiation in lens development. / Cavalheiro, Gabriel R.; Matos-Rodrigues, Gabriel E.; Zhao, Yilin; Gomes, Anielle L.; Anand, Deepti; Predes, Danilo; de Lima, Silmara; Abreu, Jose G.; Zheng, Deyou; Lachke, Salil A.; Cvekl, Ales; Martins, Rodrigo A.P.

In: Developmental Biology, Vol. 429, No. 1, 01.09.2017, p. 105-117.

Research output: Contribution to journalArticle

Cavalheiro, GR, Matos-Rodrigues, GE, Zhao, Y, Gomes, AL, Anand, D, Predes, D, de Lima, S, Abreu, JG, Zheng, D, Lachke, SA, Cvekl, A & Martins, RAP 2017, 'N-myc regulates growth and fiber cell differentiation in lens development', Developmental Biology, vol. 429, no. 1, pp. 105-117. https://doi.org/10.1016/j.ydbio.2017.07.002
Cavalheiro GR, Matos-Rodrigues GE, Zhao Y, Gomes AL, Anand D, Predes D et al. N-myc regulates growth and fiber cell differentiation in lens development. Developmental Biology. 2017 Sep 1;429(1):105-117. https://doi.org/10.1016/j.ydbio.2017.07.002
Cavalheiro, Gabriel R. ; Matos-Rodrigues, Gabriel E. ; Zhao, Yilin ; Gomes, Anielle L. ; Anand, Deepti ; Predes, Danilo ; de Lima, Silmara ; Abreu, Jose G. ; Zheng, Deyou ; Lachke, Salil A. ; Cvekl, Ales ; Martins, Rodrigo A.P. / N-myc regulates growth and fiber cell differentiation in lens development. In: Developmental Biology. 2017 ; Vol. 429, No. 1. pp. 105-117.
@article{81196a98b98444c5a25ed8db10268b69,
title = "N-myc regulates growth and fiber cell differentiation in lens development",
abstract = "Myc proto-oncogenes regulate diverse cellular processes during development, but their roles during morphogenesis of specific tissues are not fully understood. We found that c-myc regulates cell proliferation in mouse lens development and previous genome-wide studies suggested functional roles for N-myc in developing lens. Here, we examined the role of N-myc in mouse lens development. Genetic inactivation of N-myc in the surface ectoderm or lens vesicle impaired eye and lens growth, while “late” inactivation in lens fibers had no effect. Unexpectedly, defective growth of N-myc-deficient lenses was not associated with alterations in lens progenitor cell proliferation or survival. Notably, N-myc-deficient lens exhibited a delay in degradation of DNA in terminally differentiating lens fiber cells. RNA-sequencing analysis of N-myc-deficient lenses identified a cohort of down-regulated genes associated with fiber cell differentiation that included DNaseIIβ. Further, an integrated analysis of differentially expressed genes in N-myc-deficient lens using normal lens expression patterns of iSyTE, N-myc-binding motif analysis and molecular interaction data from the String database led to the derivation of an N-myc-based gene regulatory network in the lens. Finally, analysis of N-myc and c-myc double-deficient lens demonstrated that these Myc genes cooperate to drive lens growth prior to lens vesicle stage. Together, these findings provide evidence for exclusive and cooperative functions of Myc transcription factors in mouse lens development and identify novel mechanisms by which N-myc regulates cell differentiation during eye morphogenesis.",
keywords = "Cell cycle, Denucleation, Eye, Oncogene, Organogenesis, Transcription factor",
author = "Cavalheiro, {Gabriel R.} and Matos-Rodrigues, {Gabriel E.} and Yilin Zhao and Gomes, {Anielle L.} and Deepti Anand and Danilo Predes and {de Lima}, Silmara and Abreu, {Jose G.} and Deyou Zheng and Lachke, {Salil A.} and Ales Cvekl and Martins, {Rodrigo A.P.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1016/j.ydbio.2017.07.002",
language = "English (US)",
volume = "429",
pages = "105--117",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - N-myc regulates growth and fiber cell differentiation in lens development

AU - Cavalheiro, Gabriel R.

AU - Matos-Rodrigues, Gabriel E.

AU - Zhao, Yilin

AU - Gomes, Anielle L.

AU - Anand, Deepti

AU - Predes, Danilo

AU - de Lima, Silmara

AU - Abreu, Jose G.

AU - Zheng, Deyou

AU - Lachke, Salil A.

AU - Cvekl, Ales

AU - Martins, Rodrigo A.P.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Myc proto-oncogenes regulate diverse cellular processes during development, but their roles during morphogenesis of specific tissues are not fully understood. We found that c-myc regulates cell proliferation in mouse lens development and previous genome-wide studies suggested functional roles for N-myc in developing lens. Here, we examined the role of N-myc in mouse lens development. Genetic inactivation of N-myc in the surface ectoderm or lens vesicle impaired eye and lens growth, while “late” inactivation in lens fibers had no effect. Unexpectedly, defective growth of N-myc-deficient lenses was not associated with alterations in lens progenitor cell proliferation or survival. Notably, N-myc-deficient lens exhibited a delay in degradation of DNA in terminally differentiating lens fiber cells. RNA-sequencing analysis of N-myc-deficient lenses identified a cohort of down-regulated genes associated with fiber cell differentiation that included DNaseIIβ. Further, an integrated analysis of differentially expressed genes in N-myc-deficient lens using normal lens expression patterns of iSyTE, N-myc-binding motif analysis and molecular interaction data from the String database led to the derivation of an N-myc-based gene regulatory network in the lens. Finally, analysis of N-myc and c-myc double-deficient lens demonstrated that these Myc genes cooperate to drive lens growth prior to lens vesicle stage. Together, these findings provide evidence for exclusive and cooperative functions of Myc transcription factors in mouse lens development and identify novel mechanisms by which N-myc regulates cell differentiation during eye morphogenesis.

AB - Myc proto-oncogenes regulate diverse cellular processes during development, but their roles during morphogenesis of specific tissues are not fully understood. We found that c-myc regulates cell proliferation in mouse lens development and previous genome-wide studies suggested functional roles for N-myc in developing lens. Here, we examined the role of N-myc in mouse lens development. Genetic inactivation of N-myc in the surface ectoderm or lens vesicle impaired eye and lens growth, while “late” inactivation in lens fibers had no effect. Unexpectedly, defective growth of N-myc-deficient lenses was not associated with alterations in lens progenitor cell proliferation or survival. Notably, N-myc-deficient lens exhibited a delay in degradation of DNA in terminally differentiating lens fiber cells. RNA-sequencing analysis of N-myc-deficient lenses identified a cohort of down-regulated genes associated with fiber cell differentiation that included DNaseIIβ. Further, an integrated analysis of differentially expressed genes in N-myc-deficient lens using normal lens expression patterns of iSyTE, N-myc-binding motif analysis and molecular interaction data from the String database led to the derivation of an N-myc-based gene regulatory network in the lens. Finally, analysis of N-myc and c-myc double-deficient lens demonstrated that these Myc genes cooperate to drive lens growth prior to lens vesicle stage. Together, these findings provide evidence for exclusive and cooperative functions of Myc transcription factors in mouse lens development and identify novel mechanisms by which N-myc regulates cell differentiation during eye morphogenesis.

KW - Cell cycle

KW - Denucleation

KW - Eye

KW - Oncogene

KW - Organogenesis

KW - Transcription factor

UR - http://www.scopus.com/inward/record.url?scp=85025134950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85025134950&partnerID=8YFLogxK

U2 - 10.1016/j.ydbio.2017.07.002

DO - 10.1016/j.ydbio.2017.07.002

M3 - Article

C2 - 28716713

AN - SCOPUS:85025134950

VL - 429

SP - 105

EP - 117

JO - Developmental Biology

JF - Developmental Biology

SN - 0012-1606

IS - 1

ER -