The role of hypoxia and neurogenic genes (Mash-1 and Prox-1) in the developmental programming and maturation of pulmonary neuroendocrine cells in fetal mouse lung

Suzanne McGovern, Jie Pan, Guillermo Oliver, Ernest Cutz, Herman Yeger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Pulmonary neuroendocrine cells (PNECs) are the first cell type to differentiate within the primitive airway epithelium, suggesting a possible role in lung development. The differentiation of PNECs in fetal lung is governed by proneural genes such as the mammalian homolog of the achaete-scute complex (Mash-1) and a related transcription factor, hairy and enhancer of split1 (Hes-1). We examined the expression of Mash-1 and a downstream transcription factor Prox-1 in the developing mouse lung of wild-type and respective knockout mouse models. During early stages (embryonic day 12, E12) of development, only some PNECs expressed Mash-1 and Prox-1, but by E15, all PNECs coexpressed both transcription factors. PNECs failed to develop in Mash-1 but not in Prox-1-null mice, indicating that Mash-1 is essential for the initiation of the PNEC phenotype, whereas Prox-1 is associated with the development of this phenotype. As lung develops within a low O 2 environment (fetal euoxia, pO 2 20 to 30 mm Hg), we examined the effects of hypoxia on PNEC differentiation. Organ cultures of fetal mouse lungs at E12 and E16 were maintained under either 20% O 2 (normoxia, Nox) or 5% O 2 (hypoxia, Hox) and were examined every 24 h for up to 6 days in culture. In E12 explants, Hox enhanced branching morphogenesis and increased cell proliferation, but PNEC numbers and Mash-1 expression were significantly reduced. This effect could be reversed by switching the explants back to Nox. In contrast, Hox had no apparent effect on Hes-1 expression. Similarly, Hox had no effect on airway branching, PNEC numbers, or Mash-1 expression in E16 explants, indicating locked-in developmental programming. We suggest that during early stages of lung development, pO 2 concentration in concert with neurogenic gene expression modulates PNEC phenotype. Thus, disturbances in intrauterine pO 2 homeostasis could alter the functional maturation of the PNEC system and hence be involved in the pathogenesis of various perinatal pulmonary disorders.

Original languageEnglish (US)
Pages (from-to)180-195
Number of pages16
JournalLaboratory Investigation
Volume90
Issue number2
DOIs
StatePublished - Feb 2010

Keywords

  • Branching morphogenesis
  • Mash-1
  • Normoxia/hypoxia
  • PNEC/NEB development
  • Prox-1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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