Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation.
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.
Okubo
Tadashi
T
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Knoepfler
Paul S
PS
Eisenman
Robert N
RN
Hogan
Brigid L M
BL
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D017930:Genes, Reporter; D006609:High Mobility Group Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000196:embryology*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D037721:Pulmonary Surfactant-Associated Protein C; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D055758:SOX9 Transcription Factor; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D006609:High Mobility Group Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; D037721:Pulmonary Surfactant-Associated Protein C; D011993:Recombinant Fusion Proteins; D055758:SOX9 Transcription Factor; C489680:Sftpc protein, mouse; C527933:Sox9 protein, mouse; D014157:Transcription Factors