Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice

Abstract

In most mammals the pancreas develops from the foregut endoderm as ventral and dorsal buds. These buds fuse and develop into a complex organ composed of endocrine, exocrine and ductal components. This developmental process depends upon an integrated network of transcription factors. Gene targeting experiments have revealed critical roles for Pdx1, Isl1, Pax4, Pax6 and Nkx2-2 (refs 3,4,5,6,7, 8,9,10). The homeobox gene HLXB9 (encoding HB9) is prominently expressed in adult human pancreas, although its role in pancreas development and function is unknown. To facilitate its study, we isolated the mouse HLXB9 orthologue, Hlxb9. During mouse development, the dorsal and ventral pancreatic buds and mature beta-cells in the islets of Langerhans express Hlxb9. In mice homologous for a null mutation of Hlxb9, the dorsal lobe of the pancreas fails to develop. The remnant Hlxb9-/- pancreas has small islets of Langerhans with reduced numbers of insulin-producing beta-cells. Hlxb9-/- beta-cells express low levels of the glucose transporter Glut2 and homeodomain factor Nkx 6-1. Thus, Hlxb9 is key to normal pancreas development and function.

Directed differentiation of human embryonic stem cells towards a pancreatic cell fate

“…Although the exact mechanism underlying this phenomenon is not clear, we speculate that RA may facilitate the conversion of mesendoderm or endoderm into pancreatic endoderm in our system. This is further supported by our observation that RA increased the expression of HLXB9, which is expressed in the dorsal bud of the developing mouse pancreas prior to the onset of Pdx1 expression [39,40]. However, we cannot rule out the possibility that RA simply increased the endodermal population at the expense of mesodermal differentiation, and the increased expression of PDX1 resulted from differentiation of the enriched endodermal population.…”

Pancreas organogenesis: From bud to plexus to gland

“…In Mnx1 null mice, ventral pancreas development proceeds normally, producing all pancreatic cell types, but with reduced b-cell numbers and increased d-cells. Those b-cells that do develop in the ventral bud are immature in that they lack Pdx1, Nkx6.1, and GLUT2 Harrison et al, 1999). We propose that further studies of the different functions of Mnx1 during the various phases of development, and the apparent variation between its role in the two buds are highly warranted.…”

“…In the 8-somite stage ($E8) mouse embryo, Mnx1 is expressed within the notochord and the entire dorsal and ventral endoderm at the prospective pancreatic level Harrison et al, 1999). Endodermal Mnx1 expression was reported to be transient and forming a dorsal-ventral gradient at E9.5 (Sherwood et al, 2009), with expression remaining in both pancreatic buds and the stomach until E12.5.…”

“…More recent analysis (Pan and Wright, unpublished data) suggests that Mnx1 is not down-regulated but becomes redistributed to discrete pancreatic epithelium domains at E12.5, with its later expression becoming confined to Pax6 þ endocrine precursors during the secondary transition. In adult pancreas, Mnx1 is expressed in mature b-cells Harrison et al, 1999).…”

Calsenilin is required for endocrine pancreas development in zebrafish

“…The demonstration of the crucial role of Pdx1 in pancreas development was followed by gene targeting of many other genes revealing the functional importance of several transcription factors at various stages of pancreas development. These factors include the Lim homeodomain protein Isl-1 (Ahlgren et al, 1997); the paired box genes Pax4 and Pax6 (SosaPineda et al, 1997;StOnge et al, 1997); the bHLH genes NeuroD and Neurogenin3 (Naya et al, 1997;Gradwohl et al, 2000); the NK homeobox genes Nkx2.2, Nkx6.1, Nkx6.2 (Sussel et al, 1998;Sander et al, 2000;Henseleit et al, 2005); and the homeobox gene Hb9 (Harrison et al, 1999;Li et al, 1999). Pancreas development is also tightly controlled by signaling molecules derived from adjacent mesodermal structures.…”