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

Tadashi Okubo, Paul S Knoepfler, Robert N. Eisenman, Brigid L M Hogan

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1363-1374
Number of pages12
JournalDevelopment
Volume132
Issue number6
DOIs
StatePublished - Mar 2005
Externally publishedYes

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Cell Differentiation
Stem Cells
Cell Proliferation
Lung
S Phase
Epithelium
Bronchopulmonary Dysplasia
Proto-Oncogenes
Mesoderm
Protein C
Surface-Active Agents
Population
Lung Neoplasms
Cell Cycle
Up-Regulation
Embryonic Structures
Epithelial Cells
Apoptosis
Growth
Genes

Keywords

  • Conditional inactivation
  • Differentation
  • Growth
  • Lung development
  • Nmyc
  • Progenitor cells
  • Sox proteins

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation. / Okubo, Tadashi; Knoepfler, Paul S; Eisenman, Robert N.; Hogan, Brigid L M.

In: Development, Vol. 132, No. 6, 03.2005, p. 1363-1374.

Research output: Contribution to journalArticle

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