Regulation of Pax4 Paired Homeodomain Gene by Neuron-restrictive Silencer Factor

Abstract

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.