During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing β-cells1–3. However, the exact mechanisms by which the lactogenic hormones drive β-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive β-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in β-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked β-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gαq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gαi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked β-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking β-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes4.

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During pancreas development, both the exocrine and endocrine lineages differentiate from a common pool of progenitor cells with similarities to mature pancreatic duct cells. A small set of transcription factors, including Tcf2, Onecut1, and Foxa2, has been identified in these pancreatic progenitor cells. The Sry/HMG box transcription factor Sox9 is also expressed in the early pancreatic epithelium and is required for normal pancreatic exocrine and endocrine development in humans. In this study, we found Sox9 in mice specifically expressed with the other progenitor transcription factors in both pancreatic progenitor cells and duct cells in the adult pancreas. Sox9 directly bound to all three genes in vitro and in intact cells, and regulated their expression. In turn, both Foxa2 and Tcf2 regulated Sox9 expression, demonstrating feedback circuits between these genes. Furthermore, Sox9 activated the expression of the proendocrine factor Neurogenin3, which also depends on the other members of the progenitor transcription network. These studies indicate that Sox9 plays a dual role in pancreatic progenitor cells: both maintaining a stable transcriptional network and supporting the programs by which these cells differentiate into distinct lineages.

To investigate the role of the Sry/hydroxymethylglutaryl box (Sox) transcription factors in the development of the pancreas, we determined the expression pattern of Sox factors in the developing mouse pancreas. By RT-PCR, we detected the presence of multiple Sox family members in both the developing pancreas and mature islets and then focused on two factors, Sox2 and Sox4. The expression field of Sox2, which plays a role in the maintenance of some stem cell populations, included the developing duodenum, but Sox2 was specifically excluded from the pancreatic buds. In contrast, Sox4 was detected broadly in the early pancreatic buds and eventually became restricted to the nuclei of all islet cells in the adult mouse. Mice homozygous for a null mutation of the sox4 gene showed normal pancreatic bud formation and endocrine cell differentiation up to embryonic day 12.5. Beyond that date, cultured pancreatic explants lacking sox4 failed to form normal islets. Instead, a markedly reduced number of endocrine cells were found scattered through the explant. We show here that several Sox transcription factors are expressed in the developing pancreas and in the islet, and that one of these factors, Sox4, is required for the normal development of pancreatic islets. Diabetes 54:3402-3409, 2005 S cattered through the exocrine pancreas, the islets of Langerhans are highly organized clusters of endocrine cells comprised of four distinct cell types: the glucagon-secreting ␣-cells, the insulinsecreting ␤-cells, the somatostatin-secreting ␦-cells, and the pancreatic polypeptide-secreting cells. Because of the essential role of the islet hormones in energy metabolism, defects in the development, maintenance, or function of the endocrine pancreas have serious consequences, including diabetes.The pancreas forms from the endoderm in the region of the foregut/midgut junction and is first visible in mice at embryonic day 9.5 (e9.5) (1). The first endocrine cells of the pancreas appear at around e9.5 in the dorsal pancreatic bud. These cells express glucagon; a few insulinexpressing cells appear ϳ1 day later. At ϳe13-14, the pancreas undergoes a distinct change termed the secondary transition, characterized by the appearance of ductal cells, exocrine cells, and delta cells and a rapid expansion of the insulin-expressing cells. The endocrine cells found in the pancreas before the secondary transition have clear differences from mature islet cells and may result from developmental pathways that are distinct from those that produce the more mature endocrine cells that arise following the secondary transition (2-6). By e18, the first pancreatic polypeptide-expressing cells appear, and the endocrine cells organize into distinct islets with the ␤-cells forming the central core. Around the same time, ␤-cell neogenesis declines, but the simultaneous onset of ␤-cell replication continues to expand the ␤-cell population and enlarge the forming islets (7).This process of endocrine cell determination and differentiation depends on the proper sequentia...

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