College Papers

Organogenesis SOX) signals specify the endodermal epithelium of

Organogenesis of the pancreas is exclusively studied in several vertebrate species such as rodents, sheep, and chick. These studies effort was defining conserved developmental pathways which have an impact on the timing of morphological changes and differentiation of endocrine and exocrine cells. During patterning of the endoderm, the developing gut tube subdivided into organ-specific areas. In mice, inductive extrinsic (Notch, FGF, TGF-beta, and Wnt) and intrinsic (PDX1, IA1, NKX, PAX, and SOX) signals specify the endodermal epithelium of the foregut to dorsal (DP) and ventral (VP) buds, contributing to the pancreas formation. Several studies developed transgenic animal models for research on pancreatic cell lineage, exocrine and endocrine secretions, in addition to regulatory factors which are involved in these procedures; with the aim of diabetes mellitus therapy and pancreatic cancer treatment. These findings require translation to humans because of some differences between the human and the mice in pancreas development during fetal growth. Interestingly, sheep represents a large mammalian model system sharing similarities in fetal physiology and development with the human, especially in long gestational period. Also, beta cell differentiation and proliferation occur simultaneously during pancreas development in sheep, comparable with the time axis for endocrine formation in the human.(Limesand)

Pancreatic and duodenal homeobox factor 1 (Pdx1) (also known as IDX-1, STF-1 or IPF-1), which expresses at the entire early pancreas and part of the surrounding gut tube has a key role in an early pancreatic specification. In adults, this gene expression restricted only in the beta cells and act as a transactivator of beta cell-specific genes including insulin, glucokinase, islet amyloid polypeptide (IAPP), and glucose transporter type 2 (Glut2) (Leonard et al. 1993;Ohlsson et al. 1993; Serup et al. 1995; Waeber et al. 1996; Watada et al. 1996a,b). Pdx1 knock-out mouse embryos are largely deficient in a pancreas and could not alive after birth.  However, a small dorsal bud with a few glucagon expressing cells is present without insulin expression. (Jonsson et al. 1994; Offield et al. 1996). In humans, heterozygous mutations in PDX1 gene predispose to MODY (Maturity Onset Diabetes of the Young). Whereas, the homozygous mutation for a cytosine deletion in codon 63 of PDX1 causes a frameshift mutation resulting in pancreatic agenesis (Stoffers et al., 1997). Although pdx1 operates as a crucial regulator of pancreatic beta-cell genes, the molecular basis of its expression and regulation determined by mapping Pdx1 gene in different spices. As PDX1 function appears to be very similar in rodents and human, the 5′ flanking conserved sequences of the gene corresponding to several enhancer-like regions, would be of importance for its expression. Pdx1 gene expression is regulated by TATA-less promoter; thus, it utilizes multiple transcriptions start sites. Potential transcription factor binding sites for bHLH/ bHLH-ZIP proteins (E-box), CTF/NF-1 (CAAT), and C/EBP are located upstream of the major start site (Sharma S, 1996). The analysis of PDX1-driven reporter constructs in transgenic mice revealed that approximately 4.5 kb of genomic fragment upstream of mouse PDX1 initiation start site, contains cis-regulatory elements, and in addition to conserved proximal promoter sequences could be essential for its transcriptional control. These highly homologous regions referred to as Area I, II, III and located between _2.7 and _1.8 kb of mouse PDX1 gene (Gerrish, ). Identical regions were found between _2.81 and _1.67 kb of the human Pdx-1 gene, PH1, PH2, and PH3 for PDX-1 homologous regions 1–3 (22).

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