1: J Biol Chem. 2003 Sep 12;278(37):35057-62. Epub 2003 Jun 26. 

Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer
factor.

Kemp DM, Lin JC, Habener JF.

Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard
Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02114,
USA. daniel.kemp@pharma.novartis.com

An elucidation of the key regulatory factors in pancreas development is critical
for understanding the pathogenesis of diabetes mellitus. This study examined
whether a specific regulatory mechanism that exists in neuronal development also
plays a role in the pancreas. In non-neuronal cells, neuron-restrictive silencer
factor (NSRF) actively represses gene transcription via a sequence-specific DNA
motif known as the neuron-restrictive silencer element (NRSE). This DNA motif
has been identified in many genes that are specific markers for cells of
neuronal and neuroendocrine lineage. We identified several genes involved in
pancreas development that also harbor NRSE-like motifs, including pdx-1,
Beta2/NeuroD, and pax4. The paired homeodomain transcription factor Pax4 is
implicated in the differentiation of the insulin-producing beta-cell lineage
because disruption of the pax4 gene results in a severe deficiency of beta-cells
and the manifestation of diabetes mellitus in mice. The NRSE-like motif
identified in the upstream pax4 promoter is highly conserved throughout
evolution, forms a DNA-protein complex with NRSF, and confers NRSF-dependent
transcriptional repression in the context of a surrogate gene promoter. This
cis-activating NRSE element also confers NRSF-dependent modulation in the
context of the native pax4 gene promoter. Together with earlier reports, these
new findings suggest an important functional role for NRSF in the expression of
the pax4 gene and infer a role for NRSF in pancreatic islet development.

PMID: 12829700 [PubMed - indexed for MEDLINE]


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