Considerable progress has been made in the understanding of the sequential activation of signal transduction pathways and the expression of transcription factors during pancreas development. Much of this understanding has been obtained by analyses of the phenotypes of mice in which the expression of key genes has been disrupted (knockout mice). Knockout of the genes for Pdx1, Hlxb9, Isl1, or Hex results in an arrest of pancreas development at a very early stage (embryonic d 8-9). Disruption of genes encoding components of the Notch signaling pathway, e.g. Hes1 or neurogenin-3, abrogates development of the endocrine pancreas (islets of Langerhans). Disruption of transcription factor genes expressed more downstream in the developmental cascade (Beta2/NeuroD, Pax4, NKx2.2, and Nkx6.1) curtails the formation of insulin-producing beta-cells. An understanding of the importance of transcription factor genes during pancreas development has provided insights into the pathogenesis of diabetes, in which the mass of insulin-producing beta-cells is reduced.

Transcription factors provide the genetic instructions that drive pancreatic development and enable mature beta cells to function properly. To understand fully how this is accomplished, it is necessary to unravel the regulatory networks formed by transcription factors acting on their genomic targets. This article discusses recent advances in our understanding of how transcriptional networks control early pancreas organogenesis, embryonic endocrine cell formation and the differentiated function of adult beta cells. We discuss how mutations in several transcription factor genes involved in such networks cause Maturity onset diabetes of the young (MODY). Finally, we propose that pancreatic gene programs might be manipulated to generate beta cells or to enhance the function of existing beta cells, thereby providing a possible treatment of different forms of diabetes.

Many transcription factors are critical for ensuring proper embryonic development of the endocrine pancreas and normal islet function. The transcription factor pancreatic duodenal homeobox 1 (PDX-1) is uniformly expressed in early pancreatic buds of embryos as well as the beta and delta cells of the islets of Langerhans. PDX-1 has also been found in dispersed endocrine cells of the duodenum in adults and plays a key role in pancreas formation. It has been reported that null mutation of PDX-1 in mice results in a failure of the pancreatic bud to expand; thus, the mice die 2-3 days after birth from hyperglycemia and dehydration. Heterozygous PDX-1 mice developed a pancreas but were diabetic. It has been shown that PDX-1 is required for maintaining the pancreatic islet functions by activating gene transcriptions including insulin, somatostatin (SST), islet amyloid polypeptide, glucose transporter type 2, and glucokinase. PDX-1 serves a dual role in pancreatic development. It initially contributes to pancreatic formation during embryogenesis and subsequently regulates the pancreatic islet cell physiology in mature islet cells. Understanding the underlying molecular mechanisms of pancreas formation, especially the function of PDX-1, may contribute to the enhanced treatment and prevention of debilitating diseases such as diabetes, insulinomas, and pancreatic carcinomas.