Maria E. Wilson

Gene expression cascades in pancreatic development

The specialized endocrine and exocrine cells of the pancreas originally derive from a pool of apparently identical cells in the early gut endoderm. Serial changes in their gene expression program, controlled by a hierarchy of pancreatic transcription factors, direct this progression from multipotent progenitor cell to mature pancreatic cell. When the cells differentiate, this hierarchy of factors coalesces into a network of factors that maintain the differentiated phenotype of the cells. As we develop an understanding of the pancreatic transcription factors, we are also acquiring the tools with which we can ultimately control pancreatic cell differentiation.

Rfx6 directs islet formation and insulin production in mice and humans

Insulin from the β-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the β-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate β-cells for patients with diabetes.

Sox9 coordinates a transcriptional network in pancreatic progenitor cells

During pancreas development, both the exocrine and endocrine lineages differentiate from a common pool of progenitor cells with similarities to mature pancreatic duct cells. A small set of transcription factors, including Tcf2, Onecut1, and Foxa2, has been identified in these pancreatic progenitor cells. The Sry/HMG box transcription factor Sox9 is also expressed in the early pancreatic epithelium and is required for normal pancreatic exocrine and endocrine development in humans. In this study, we found Sox9 in mice specifically expressed with the other progenitor transcription factors in both pancreatic progenitor cells and duct cells in the adult pancreas. Sox9 directly bound to all three genes in vitro and in intact cells, and regulated their expression. In turn, both Foxa2 and Tcf2 regulated Sox9 expression, demonstrating feedback circuits between these genes. Furthermore, Sox9 activated the expression of the proendocrine factor Neurogenin3, which also depends on the other members of the progenitor transcription network. These studies indicate that Sox9 plays a dual role in pancreatic progenitor cells: both maintaining a stable transcriptional network and supporting the programs by which these cells differentiate into distinct lineages.

Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas.

The earliest endocrine cells in the developing pancreas make glucagon and are described as alpha cells. We show here that these cells express islet amyloid polypeptide and prohormone convertase 1/3 (PC1/3), proteins that are not expressed by mature alpha cells, but are found in beta cells. PC1/3 converts proglucagon to the functionally distinct hormones glucagon-like peptide (GLP)-1 and GLP-2 rather than glucagon. Despite these differences, the early proglucagon-positive cells express, as do mature alpha cells, the POU domain transcription factor Brn-4, and do not express the beta cell factor pdx-1. The early production of atypical peptide hormones by these cells suggests that they could play an important role locally or systemically in the development of the embryo.