Genetic analysis of MFng in mouse pancreas

The pancreas is an endodermally derived organ consisting of three major cell lineages. The endocrine cells, organised into the Islets of Langerhans, regulate blood glucose homeostasis by producing and secreting hormones such as glucagon and insulin into the bloodstream. The major part of the pancreas consists however of acinar cells that produce digestive enzymes that are transported via a highly branched ductal system to the duodenum where they function in breakdown of food. Early in pancreas development a dorsal and ventral evagination of the foregut epithelium appear, resulting in the formation of the dorsal and ventral pancreatic bud. These pancreatic buds subsequently grow, branch and differentiate to form the mature pancreas via a process controlled by intrinsic factors, such as transcription factors, and extracellular signals. Insulin promoter factor 1 (Ipf1), also known as Pdx1 (for Pancreatic duodenal homeobox gene 1), is required for pancreas development. Although the evagination of pancreatic buds still occurs in Ipf1/Pdx1 mutant mice, the subsequent proliferation, branching and differentiation is impaired, resulting in complete pancreatic agenesis. Gene array profiling identified several candidate Ipf1/Pdx1 target genes, including FgfR2IIIb, ErbB3, Ptf1a/p48, Pax6 and Nkx6.1, in pancreatic progenitor cells. Together these genes provide a mechanistic explanation for the pancreatic growth arrest observed in Ipf1/Pdx1 deficient mice. In addition, Spondin1, which has not previously been described in the pancreas, was identified to be regulated by Ipf1/Pdx1. The spatial and temporal expression pattern of Spondin1 defines Spondin1 as a marker for early pancreatic progenitor cells. The Notch signalling pathway controls cell type specification and differentiation during pancreas development. The Fringe family of proteins have previously been shown to regulate Notch signalling by altering the interaction between Notch receptors and their ligands, hence affecting the cellular response. Manic Fringe (MFng) is transiently expressed in pancreatic pro-endocrine cells between E9.5 and E14.5. The expression of MFng is regulated by Ngn3, which may suggest a role for MFng in pro-endocrine cell maturation. The lack of a pancreatic phenotype in transgenic mice overexpressing MFng in the pancreatic epithelium and in MFng null mutant mice, however, provide evidence that MFng is dispensable for the specification, differentiation and function of the adult pancreas. Inhibitors of DNA binding (Id) proteins are generally known as inhibitors of differentiation, a feature they mainly perform by forming non-functional heterodimers with bHLH proteins, thereby inhibiting downstream targets of the bHLH proteins. Id proteins also promote cell proliferation by interacting with the cell cycle machinery. In the developing pancreas Id2 and Id3 are co-expressed in an overlapping manner during the period of massive proliferation and expansion of the pancreatic epithelium, suggestive of a role for the Id proteins during these processes. In addition, Id4 expression is also detected in the embryonic pancreas, albeit at lower levels. Gain- and loss- of- function analyses suggest however that specification, differentiation and function of the adult pancreas are largely independent of Id function.