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Section 2: ß-Cell Genes: Functional Aspects

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Section 2: ß-Cell Genes: Functional Aspects Section 2: ␤-Cell Genes: Functional Aspects Regulation of pdx-1 Gene Expression Danielle Melloul, Sonya Marshak, and Erol Cerasi The homeodomain-containing transcription factor pan- tion of the endoderm, it is crucial for the development creatic duodenal homeobox 1 (PDX-1) plays a key role of endocrine and exocrine cell types (2,6). Differentiation in pancreas development and in ␤-cell function. Up- and maintenance of the ␤-cell phenotype also require stream sequences of the gene up to about ؊6 kb show PDX-1. In mice, ␤-cell–selective disruption of pdx-1 led to islet-specific activity in transgenic mice. Attempts to the development of diabetes with increasing age and was identify functional regulatory elements involved in the associated with reduced insulin and GLUT2 expression controlled expression of the pdx-1 gene led to the (7). Indeed, mice heterozygous for pdx-1 were found to be ␤ identification of distinct distal -cell–specific enhanc- glucose intolerant (7,8). In transgenic mice expressing ers in human and rat genes. Three additional sequences, ؅ an antisense ribozyme specific for mouse pdx-1 in the conserved between the mouse and the human 5 -flank- ␤ ing regions, two of which are also found in the chicken -cells, the expression of the endogenous gene was de- gene, conferred ␤-cell–specific expression on a reporter creased and followed by impaired glucose tolerance and gene, albeit to different extents. A number of transcrip- elevated glycated hemoglobin levels (9). Impaired expres- tion factors binding to and modulating the transcrip- sion of PDX-1 as a consequence of hyperglycemia or tional activity of the regulatory elements were increased lipid concentrations (10) is associated with identified, such as hepatocyte nuclear factor (HNF)-3␤, diabetes. HNF-1␣, SP1/3, and, interestingly, PDX-1 itself. A fourth In humans, a subpopulation of type 2 diabetes is mono- conserved region was localized to the proximal pro- genic and carries mutations in genes important for normal moter around an E-box motif and was found to bind ␤-cell function. Heterozygous individuals carrying one of members of the upstream stimulatory factor (USF) the mutant genes develop a form of maturity-onset diabe- family of transcription factors. We postulate that dis- ruption of pdx-1 cis-acting regulatory sequences and/or tes of the young (MODY). MODY4 has been linked to mutations or functional impairment of transcription heterozygosity for mutations in pdx-1 (11,12). Other mo- factors controlling the expression of the gene can lead nogenic forms of MODY have been associated with muta- to diabetes. Diabetes 51 (Suppl. 3):S320–S325, 2002 tions in genes coding for transcription factors hepatocyte nuclear factor (HNF)-1␣, HNF-1␤, HNF-4␣, and Beta2 (13), most of which will be described below as regulators of pdx-1 gene transcription. Together, these data indicate ancreatic duodenal homeobox 1 (PDX-1) is an that PDX-1 has a dosage-dependent regulatory effect on orphan homeodomain protein that plays an im- the expression of ␤-cell–specific genes and therefore as- portant role in pancreas development. It is ini- sists in the maintenance of euglycemia. As a consequence, Ptially detected on embryonic day 8.5 in the part of mutations or functional impairment of other transcription the dorsal and ventral primitive gut epithelium that later factors that control the expression of the pdx-1 gene in the develops into the pancreas. A high expression is main- ␤-cell could result in additional subtypes of MODY or be tained in most epithelial cells of the pancreatic bud until candidates for susceptibility to diabetes. Because PDX-1 day embryonic day 10.5 and then decreases to later appears to play such a central role in ␤-cell differentiation ␤ reappear predominantly in the differentiated -cell. Tar- and function, as well as in pancreatic regeneration (14), geted inactivation of this gene in the mouse (1,2) as well as understanding the molecular basis of its regulation and its its mutation in humans (3) result in agenesis of the maintained expression in the ␤-cell will enable the identi- pancreas. In the mouse model, malformations in areas fication of factors that govern these processes. within the duodenum and absence of Brunner’s glands were observed (1,2,4,5). Although pdx-1 gene expression does not appear to be required for pancreatic determina- STRUCTURE OF THE pdx-1 GENE The coding region of the pdx-1 gene comprises two exons. The first exon encodes for the NH2-terminal region of From the Department of Endocrinology and Metabolism, Hadassah University PDX-1, and the second encodes for the homeodomain and Hospital, Jerusalem, Israel. Address correspondence and reprint requests to Dr. Danielle Melloul, COOH-terminal domain. The human, mouse, and rat genes Department of Endocrinology, Hadassah University Hospital, P.O. Box 12 000, are localized on chromosomes 13 (15,16), 5 (17), and 12 Jerusalem 91120. E-mail: [email protected]. Received for publication 16 April 2002 and accepted in revised form 8 May (18), respectively. Although the activation domain of 2002. PDX-1 is contained within the NH2-terminal domain, its HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the homeodomain is involved in DNA binding; both are in- young; PDX-1, pancreatic duodenal homeobox 1. The symposium and the publication of this article have been made possible volved in protein–protein interactions (19–25). The pdx-1 by an unrestricted educational grant from Servier, Paris. gene is TATA-less; thus, it utilizes three principal tran- S320 DIABETES, VOL. 51, SUPPLEMENT 3, DECEMBER 2002 D. MELLOUL, S. MARSHAK, AND E. CERASI scription initiation sites (17), followed by a short 5Ј proximal duodenum and pyloric glands of the distal stom- untranslated sequence of ϳ100 nucleotides. ach and coincided with the expression of pdx-1 mRNA. Occasionally, ectopic activity was observed in exocrine tissue of the adult pancreas, submucosal layer of the REGULATION OF pdx-1 EXPRESSION duodenum, and even in the spleen (28). Distal rat and human pdx-1 enhancer elements. To Failure of the pancreas to develop in both humans and understand the mechanisms that control the expression of mice lacking PDX-1, as well as the dosage-dependent PDX-1 during pancreas development and in the adult effect of PDX-1 on the expression of ␤-cell–specific genes ␤-cell, the pdx-1 gene from different species was mapped. (and on the maintenance of euglycemia), led to the as- Regulatory regions lying upstream from the transcription sumption that sequences conserved between the two start sites are under characterization in transgenic mice as species could be essential for its transcriptional control. A well as in cultured cells in several laboratories. A genomic striking divergence at the nucleotide level was observed ϳ Ј fragment containing 6.5 kb of the 5 -flanking rat pdx-1 between the two species with the exception of four ␤ sequence was sufficient to target -galactosidase expres- regions that showed significant (94, 81, 73, and 78%) sion to pancreatic islets and duodenal cells in transgenic similarity. In addition to the conserved proximal promoter mice (17). A longer fragment containing the coding region Ј sequence (20), three short highly homologous regions and the 3 -flanking sequences of the gene restored the were found between Ϫ2.81 and Ϫ1.67 kb of the human and development of all pancreatic lineages and corrected Ϫ Ϫ between Ϫ2.7 and Ϫ1.8 kb of the mouse pdx-1 gene (Fig. glucose intolerance in pdx-1 / animals (24). In tran- 1). These regions were designated PH1, PH2, and PH3 for siently transfected ␤-cells, the fragment extending from PDX-1 homologous regions 1–3 (22) or areas I, II, and III, Ϫ6.2 to ϩ68 linked to a reporter gene showed 20- to 100-fold higher activity than that in non-islet cells. Using as determined by Gerrish et al. (31). In transient transfec- ␤ tion experiments, each of the conserved sequences was deletion analyses, the -cell–specific regulated expression ␤ of the rat sequence appeared to require a distal enhancer able to confer -cell–specific activity on a heterologous element located between the Ϫ6.2- and Ϫ5.67-kb region of promoter; however, it was done to different extents. the gene. This element was shown to bind the endodermal PH1/areaI and PH2/areaII showed the highest preferential ␤ ␤ factors HNF-3␤ and Beta2, which act cooperatively to induction in -cell versus non– -cell activity (22,31). An induce PDX-1 expression. Furthermore, glucocorticoids interesting observation was the absence of the PH2/areaII Ј reduced pdx-1 gene expression by interfering with domain in the chicken 5 -flanking region (31), suggesting HNF-3␤ activity on the islet enhancer (26). that the regulation of pdx-1 expression in birds may differ To characterize the regulatory elements and potential from that in rodents and humans. transcription factors necessary for the expression of hu- Attempting to identify factors that regulate the tran- man pdx-1 in ␤-cells, a series of 5Ј and 3Ј deletion scriptional activity of the conserved domains, DNase I fragments of a 7-kb sequence of the 5Ј-flanking region of footprinting analyses, gel electrophoretic mobility shift the gene, fused to a reporter gene, was tested. By transient assays and mutational studies led to the identification of transfections in ␤-cells and non–␤-cells, a ␤-cell–specific several transcription factors (Fig. 1). PH1/areaI and PH2/ distal enhancer element located between Ϫ3.7 and Ϫ3.45 areaII sequences bind and are transactivated by HNF-3␤. kb was delineated. This enhancer fragment strongly stim- Although mutations in the HNF-3␤ binding site within the ulated reporter gene activity in all ␤-cell lines tested and PH2/areaII sequence did not modify its transcriptional was much less active in non–␤-cells, including glucagon- activity, in PH1/areaI, it had a profound effect.
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