Minireview: Transcriptional Regulation in Pancreatic Development

0013-7227/05/$15.00/0 Printed in U.S.A. Endocrinology 146(3):1025–1034 Copyright © 2005 by The Endocrine Society doi: 10.1210/en.2004-1576 Minireview: Transcriptional Regulation in Pancreatic Development Joel F. Habener, Daniel M. Kemp, and Melissa K. Thomas Laboratory of Molecular Endocrinology, Massachusetts General Hospital (J.F.H., M.K.T.), Howard Hughes Medical Institute (J.F.H.), Harvard Medical School (J.F.H., M.K.T.), Boston, Massachusetts 02114; and Novartis Institutes for BioMedical Research (D.M.K.), Cambridge, Massachusetts 02139 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 devel- R ECENT STUDIES OF the biology of pancreas development have shed new light on the cause of type 2 diabetes. The identification of transcription factors involved in regulation of the expression of key genes required in the developing and adult endocrine and exocrine pancreas has been provided by observing the phenotypic consequences of targeted disruptions of the genes (gene knockouts) encoding these factors in mice. Remarkably, almost without exception, disruption of these genes has resulted in phenotypes of impaired development of the pancreas and consequent diabetes. Furthermore, lessons learned from the gene knockouts in mice have been used to successfully identify mutations in several of the corresponding orthologous genes in individuals with familial monogenic type 2 diabetes. In this minireview we attempt to encapsulate a rapidly growing body of knowledge that is providing insight into the genetic contributions to the development of diabetes. The thematic emphasis is on the impact that genetic polymorphisms or mutations in genes encoding transcription factors essential for pancreas development have on predisposition for diabetes. For more comprehensive, in-depth information on this topic, the reader is referred to several recent excellent reviews (1–9). Anatomical and Morphological Development of the Pancreas The pancreas consists of three main tissue cell types (in addition to vascular and stromal supporting tissues): the First Published Online December 16, 2004 Abbreviations: bHLH, Basic helix-loop-helix; e, embryonic day; HNF, hepatic nuclear factor; MODY, maturity-onset diabetes of the young; Ngn, neurogenin. Endocrinology is published monthly by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community. opment 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 insulinproducing ␤-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 ␤-cells is reduced. (Endocrinology 146: 1025–1034, 2005) exocrine acinar tissue that produces digestive enzymes; the endocrine cells (islets of Langerhans) that produce the hormones involved in nutrient homeostasis, such as insulin and glucagon; and the elaborately branched ductal tree (10). The pancreas originates early in development [embryonic d 8.5 (e8.5) to e9.5 in the mouse] by the outcropping of two buds (ventral and dorsal) of cells from a specialized prepatterned endodermal epithelium located in the region of the foregut that is to become the duodenum (Fig. 1). By e10.5, the partially differentiated epithelium of the two buds undergoes branching morphogenesis into a ductal tree that by e12.5 results in the formation of two primordial pancreas organs consisting predominantly of an undifferentiated ductal epithelium (first developmental transition). Between e13 and e14, the dorsal and ventral pancreata rotate and fuse into a single organ. During e14.5 and e15.5, the exocrine pancreas differentiates from the ductal epithelium; on e15.5, acini are clearly discernible from ducts. Endocrine cells are present from the very beginning of development (e9.5), but up until e14 they are arrayed as single cells within the ductal epithelium, after which they undergo extensive proliferation (second developmental transition). On e16, the endocrine cells begin to organize into islet-like clusters. The islets are not fully formed until shortly before birth on e18 – e19 and undergo additional remodeling and maturation for 2–3 wk after birth (third developmental transition). The endocrine cells of the pancreas arise from stem/progenitor cells located within the early (e9.5) gut endoderm (Fig. 1). Previous ideas that pancreatic endocrine cells are derived from the neural crest have been disproved by decisive quail-chick chimera experiments, and it is now established that they are of endodermal origin. It has been shown that isolated pancreatic endodermal-derived duct cells from embryonic rat pancreas can directly differentiate into hormone-expressing cells when cultured in the presence of 1025 1026 Endocrinology, March 2005, 146(3):1025–1034 Habener et al. • Minireview FIG. 1. Schematic diagram of pancreatic development in the mouse. On e8, prepatterned endodermal epithelium of the foregut forms dorsal (DP) and ventral (VP) buds by e9.5, which then develop into branching ducts and undifferentiated epithelium (e12.5; first development transition). Single endocrine cells are interspersed among the undifferentiated epithelium. The buds begin to differentiate into endocrine and exocrine cellular lineages by e14 and proliferate and expand extensively (second development transition). By e15, the dorsal and ventral pancreases rotate, fuse, and form a nearly fully developed pancreas by e19, containing the endocrine cells organized into isolated clusters that condense into the islets of Langerhans (third developmental transition). The third transition, consisting of maturation of endocrine cells and their acquisition of full nutrient responsiveness, continues for 2–3 wk after birth. The representative transcription factors expressed during the program of development are indicated in blue and are diagrammed in a simplified developmental cascade in Fig. 2. The approximate embryonic age (in days) is designated for each stage of development. gut mesenchyme (11). The earliest endocrine cells detected in the pancreatic anlage in the foregut (e9.5) express glucagon and members of the PP-fold family of hormones, peptide YY, pancreatic polypeptide, and neurop (...truncated)