1: Development. 2005 Mar;132(6):1363-74. Epub 2005 Feb 16. 

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

Okubo T, Knoepfler PS, Eisenman RN, Hogan BL.

Department of Cell Biology, Duke University Medical Center, Durham, NC 27710,
USA.

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.

PMID: 15716345 [PubMed - indexed for MEDLINE]


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2: Dev Biol. 2004 Oct 15;274(2):271-9. 

SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli
cell precursors.

Sekido R, Bar I, Narvaez V, Penny G, Lovell-Badge R.

Division of Developmental Genetics, MRC National Institute for Medical Research,
London NW7 1AA, UK.

The Y chromosome gene Sry encodes a transcription factor required to initiate
testis development. The related autosomal gene Sox9 is up-regulated shortly
after the onset of Sry transcription and is thought essential for the
differentiation of Sertoli cells. The lineage that gives rise to Sertoli cells
has its origins within the coelomic epithelium (CE) of the genital ridge, but
from cells also able to give rise to an interstitial cell type. It was not known
at what point SRY acts in the derivation of this lineage or how the two genes
interact. To investigate the identity of the cells expressing Sry, we designed
two transgenes driven by the Sry promoter: one gives expression of a stable
reporter, human placental alkaline phosphatase (hPLAP), while the second gives
expression of a functional Myc-epitope tagged SRY protein (SRYMYC). Taking
advantage of lasting hPLAP activity after transcription of the reporter gene has
ceased, we could show that SryhPLAP was expressed exclusively in all cells fated
to become Sertoli cells. SRYMYC-single-positive cells were first observed in the
gonad and not in the CE. Subsequently, they became SRYMYC/SOX9-double-positive,
but only for a few hours before turning into SOX9-single-positive cells. After
the coelomic epithelial cells migrate into the gonad, there is first a decision
to become interstitial or supporting cells, and then the transient expression of
SRY in the latter determines their fate as Sertoli cells by up-regulating Sox9.

PMID: 15385158 [PubMed - indexed for MEDLINE]


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