GDF11 modulates NGN3+ islet progenitor cell number and promotes β-cell differentiation in pancreas development

Abstract

Identification of endogenous signals that regulate expansion and maturation of organ-specific progenitor cells is a major goal in studies of organ development. Here we provide evidence that growth differentiation factor 11(GDF11), a member of the TGF-β ligand family, governs the number and maturation of islet progenitor cells in mouse pancreas development. Gdf11 is expressed in embryonic pancreatic epithelium during formation of islet progenitor cells that express neurogenin 3. Mice deficient for Gdf11 harbor increased numbers of NGN3+ cells,revealing that GDF11 negatively regulates production of islet progenitor cells. Despite a marked expansion of these NGN3+ islet progenitors, mice lacking Gdf11 have reduced β-cell numbers and evidence of arrested β-cell development, indicating that GDF11 is also required for β-cell maturation. Similar precursor and islet cell phenotypes are observed in mice deficient for SMAD2, an intracellular signaling factor activated by TGF-β signals. Our data suggest that Gdf11 and Smad2 regulate islet cell differentiation in parallel to the Notch pathway, which previously has been shown to control development of NGN3+ cells. Thus, our studies reveal mechanisms by which GDF11 regulates the production and maturation of islet progenitor cells in pancreas development.

Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets

“…We found that the incidence of cardiac malformation and right pulmonary isomerism was significantly increased in ActRIIB Ϫ/Ϫ Smad2 ϩ/Ϫ mice compared with ActRIIB Ϫ/Ϫ mice. In addition, we demonstrated that hypoplastic islets were found not in only ActRIIB Ϫ/Ϫ but also Smad2 ϩ/Ϫ mice, which was consistent with previous studies (Kim et al, 2000;Harmon et al, 2004). Interestingly, more severe phenotypes were found in the compound heterozygous ActRIIB ϩ/Ϫ Smad2 ϩ/Ϫ mice.…”

“…It has been shown that double heterozygous mice for nodal and Smad2 exhibit similar laterality defects seen in ActRIIB Ϫ/Ϫ mice, suggesting that nodal may signal through ActRIIB and Smad2 during thoracic organ patterning (Nomura and Li, 1998). With regard to pancreas islet development, GDF11-deficient mice have been shown to exhibit hypoplasia of the islet, due to the defect in ␤ cell maturation, reminiscent of the phenotype found in Smad2 ϩ/Ϫ mice, suggesting that GDF11 uses Smad2 as a downstream signal transducer (Harmon et al, 2004). We thus speculated that Smad2 acts downstream to ActRIIB in these developmental processes, such as left-right patterning and pancreas development.…”

Regulation of muscle growth by multiple ligands signaling through activin type II receptors

“…Perhaps the most likely candidate is GDF-11͞BMP-11, which is highly related to myostatin in the mature region of the protein (2,23,24) and is also expressed in skeletal muscle. Genetic studies in mice have demonstrated clear roles for Gdf11 in regulating anterior͞posterior patterning (25), kidney development (25,26), neuronal development (27,28), and pancreas development (29). Because mice completely lacking GDF-11͞BMP-11 die during the perinatal period, however, elucidation of the role, if any, that GDF-11͞ BMP-11 plays in regulating muscle growth will require the generation of mice in which the Gdf11 gene can be deleted in either a muscle-specific or inducible manner.…”

Wnt signaling regulates pancreatic β cell proliferation

“…Light images were captured with a Zeiss (Oberkochen, Germany) Axioplan 2 microscope and software. Cell counting, point-counting morphometry, and ␤ cell quantification were performed by using standard morphometric techniques (14,44,45) or as described in SI Materials and Methods. For quantification of immunostained cells, pancreas tissue was obtained from at least four mice per genotype.…”