Transcriptomics

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Transcription profiling of mouse nmyc misexpression in lung (gain of function)


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. Experiment Overall Design: To generate Nmyc1EGF fusion protein, mouse Nmyc1 cDNA was Experiment Overall Design: inserted into the SmaI site of pEGFP (BectonDickinson), excised by Experiment Overall Design: SalI and EcoRI, and inserted into a vector containing a 3.7 kb Experiment Overall Design: promoter/enhancer of the human SFTPC gene (Wert et al., 1993). Experiment Overall Design: Transfection of 293 cells shows that the fusion protein localizes to Experiment Overall Design: the nucleus (see Fig. S1 in supplementary material). Four transgenic Experiment Overall Design: embryos were generated by pronuclear injection into Experiment Overall Design: (C57BL/6J and DBA/2J) F2 fertilized eggs. They were collected at Experiment Overall Design: E18.5, so it is not known if they would have survived postnatally. Experiment Overall Design: Duplicate samples are biological replicates.

INSTRUMENT(S): 418 [Affymetrix]

ORGANISM(S): Mus musculus  

SUBMITTER: Brian Joseph Cox  

PROVIDER: E-GEOD-6077 | ArrayExpress | 2008-06-14

SECONDARY ACCESSION(S): GSE6077GDS2406PRJNA97571

REPOSITORIES: GEO, ArrayExpress

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Publications

Integrated proteomic and transcriptomic profiling of mouse lung development and Nmyc target genes.

Cox Brian B   Kislinger Thomas T   Wigle Dennis A DA   Kannan Anitha A   Brown Kevin K   Okubo Tadashi T   Hogan Brigid B   Jurisica Igor I   Frey Brendan B   Rossant Janet J   Emili Andrew A  

Molecular systems biology 20070508


Although microarray analysis has provided information regarding the dynamics of gene expression during development of the mouse lung, no extensive correlations have been made to the levels of corresponding protein products. Here, we present a global survey of protein expression during mouse lung organogenesis from embryonic day E13.5 until adulthood using gel-free two-dimensional liquid chromatography coupled to shotgun tandem mass spectrometry (MudPIT). Mathematical modeling of the proteomic pr  ...[more]

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