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Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation.

Publication ,  Journal Article
Okubo, T; Knoepfler, PS; Eisenman, RN; Hogan, BLM
Published in: Development
March 2005

Understanding how lung progenitor cells balance proliferation against differentiation is relevant to clinical disorders such as bronchopulmonary dysplasia of premature babies and lung cancer. Previous studies have established that lung development is severely disrupted in mouse mutants with reduced levels of the proto-oncogene Nmyc, but the precise mechanisms involved have not been explored. We show here that Nmyc expression in the embryonic lung is normally restricted to a distal population of undifferentiated epithelial cells, a high proportion of which are in the S phase of the cell cycle. Overexpression of NmycEGFP in the epithelium under the control of surfactant protein C (Sftpc) regulatory elements expands the domain of S phase cells and upregulates numerous genes associated with growth and metabolism, as shown by transcriptional microarray. In addition, there is marked inhibition of differentiation, coupled with an expanded domain of expression of Sox9 protein, which is also normally restricted to the distal epithelial compartment. By contrast, conditional deletion of Nmyc leads to reduced proliferation, epithelial differentiation and high levels of apoptosis in both epithelium and mesenchyme. Unexpectedly, about 50% of embryos in which only one copy of Nmyc is deleted die perinatally, with similarly abnormal lungs. We propose a model in which Nmyc is essential in the developing lung for maintaining a distal population of undifferentiated, proliferating progenitor cells.

Duke Scholars

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Published In

Development

DOI

ISSN

0950-1991

Publication Date

March 2005

Volume

132

Issue

6

Start / End Page

1363 / 1374

Location

England

Related Subject Headings

  • Transcription Factors
  • Stem Cells
  • SOX9 Transcription Factor
  • S Phase
  • Recombinant Fusion Proteins
  • Pulmonary Surfactant-Associated Protein C
  • Proto-Oncogene Proteins c-myc
  • Peptides
  • Oligonucleotide Array Sequence Analysis
  • Mice
 

Citation

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Okubo, T., Knoepfler, P. S., Eisenman, R. N., & Hogan, B. L. M. (2005). Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation. Development, 132(6), 1363–1374. https://doi.org/10.1242/dev.01678
Okubo, Tadashi, Paul S. Knoepfler, Robert N. Eisenman, and Brigid L. M. Hogan. “Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation.Development 132, no. 6 (March 2005): 1363–74. https://doi.org/10.1242/dev.01678.
Okubo, Tadashi, et al. “Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation.Development, vol. 132, no. 6, Mar. 2005, pp. 1363–74. Pubmed, doi:10.1242/dev.01678.
Journal cover image

Published In

Development

DOI

ISSN

0950-1991

Publication Date

March 2005

Volume

132

Issue

6

Start / End Page

1363 / 1374

Location

England

Related Subject Headings

  • Transcription Factors
  • Stem Cells
  • SOX9 Transcription Factor
  • S Phase
  • Recombinant Fusion Proteins
  • Pulmonary Surfactant-Associated Protein C
  • Proto-Oncogene Proteins c-myc
  • Peptides
  • Oligonucleotide Array Sequence Analysis
  • Mice