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

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(1,2). This developmental proce ss depends upon an integrated network of transcription factors. Gene target ing experiments have revealed critical roles for Pdx1, lsl1, Pax4, Pax6 and Nkx2-2 (refs 3-10). The homeobox gene HLXB9 (encoding HB9) is prominently expressed in adult human pancreas(11), although its role in pancreas develo pment and function is unknown. To facilitate its study, we isolated the mou se HLXB9 orthologue, Hlxb9. During mouse development, the dorsal and ventra l 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 i slets of Langerhans with reduced numbers of insulin-producing p-cells. Hlxb 9(-/-) beta-cells express low levels of the glucose transporter Glut2 and h omeodomain factor Nkx 6-1. Thus, Hlxb9 is key to normal pancreas developmen t and function.