Expression, regulation and evolution of proglucagon genes in vertebrates




Busby, Ellen Rain

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Three biologically active peptide hormones, glucagon, glucagon-like peptide (GLP)-1, and GLP-2, are co-encoded by the precursor proglucagon. As all three peptides have distinct functions, regulation of proglucagon expression, translation, and processing is necessary. In all vertebrates, glucagon release from the pancreatic α-cells, leads to an increase in circulating glucose levels through liberation of glucose from the liver. Unlike glucagon, a drastic change in GLP-1 function occurs between mammals and bony fishes. In mammals, GLP-1 acts as an incretin hormone, stimulating glucose-dependent production and release of insulin from pancreatic β-cells. In fish, like glucagon, GLP-1 stimulates the hepatic release of glucose. GLP-1 may also play a role in regulation of food intake in mammals and teleosts. To date, GLP-2 function has only been determined in mammals where it acts as an intestinal growth factor. I studied two teleost species, copper rockfish (Sebastes caurinus ) and channel catfish (Ictalurus punctatus), and detected multiple forms of proglucagon regulation. First, I identified two distinct proglucagon genes, one of which does not encode GLP-2. Second, I found differential expression of the two proglucagon genes in three copper rockfish tissues, the endocrine pancreas, brain and intestine. This, along with analysis of the putative proglucagon-derived peptide sequences, suggests that the two genes encode functionally distinct proglucagon-derived peptides. Third, teleost proglucagon transcripts exhibit a form of alternative splicing whereby the GLP-2 sequence is removed from the subsequent message. Fourth, analysis of peptide production using mass spectrometry, identified the presence of some but not all peptides predicted from the mRNA, suggesting differential peptide degradation. Thus, analysis of teleost proglucagon transcripts and peptides identifies multiple levels of regulation that allow tissue specific expression and production of select proglucagon-derived peptides, demonstrating unexpected complexity of vertebrate proglucagon regulation. Identification and phylogenetic evolutionary analysis of proglucagons from teleosts, and other vertebrate groups, including elasmosbranchs, lungfish, amphibians, reptiles and mammals demonstrates the dynamic evolutionary history of proglucagon. A plethora of evolutionary processes have molded the proglucagon gene, including gene duplication, exon duplication, whole or partial exon loss, and increased sequence diversification due to duplication possibly leading to new peptide function. Thus, proglucagon is an ideal model for studying evolutionary processes and methods of functional adaptation.



Gene expression, Genetic regulation, Vertebrates, Genetics