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Signals from the neural crest regulate beta-cell mass in the pancreas

Diabetes Center, Hormone Research Institute, University of California at San Francisco, San Francisco, CA 94143, USA.
Development (Impact Factor: 6.27). 07/2008; 135(12):2151-60. DOI: 10.1242/dev.015859
Source: PubMed

ABSTRACT Pancreatic islet cells and neurons share common functions and similar ontogenies, but originate in different germ layers. To determine whether ectoderm-derived cells contribute instructive signals to the developing endoderm-derived pancreas, we defined the chronology of migration and differentiation of neural crest cells in the pancreas, and tested their role in the development of the islets. The homeodomain transcription factor Phox2b marks the neural precursors from the neural crest that colonize the gut to form the enteric nervous system. In the embryonic mouse pancreas, we found Phox2b expressed briefly together with Sox10 along the epithelial-mesenchymal border at E12.5 in cells derived from the neural crest. Downregulation of Phox2b shortly thereafter was dependent upon Nkx2.2 expressed in the adjacent pancreatic epithelium. In Phox2b(-/-) embryos, neurons and glia did not develop in the pancreas, and Nkx2.2 expression was markedly upregulated in the epithelium. In addition, the number and replication rate of insulin-expressing beta-cells increased in the Phox2b(-/-) mice. We conclude that, during pancreatic development, Phox2b and Nkx2.2 form a non-cell-autonomous feedback loop that links the neural crest with the pancreatic epithelium, regulates the size of the beta-cell population, and thereby impacts insulin-secretory capacity and energy homeostasis.

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    • "Homeobox TFs are known to be involved in embryonic and tissue developmental processes including β-cell development (Jonsson et al., 1994; Harrison et al., 1999; Nekrep et al., 2008). However, except for the mature onset of diabetes gene PDX1 (Fajans et al., 2001) and the common T2D-associated loci HHEX1 and ALX4 (Sladek et al., 2007), the inferred -9 homeobox factors have not been implicated in T2D pathogenesis. "
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    • "It is possible that co-transplantation of islet cells with neural crest stem cells (NCSCs) will promote an improved islet transplantation outcome. Indeed, recent studies have demonstrated that NCSCs have an important role in beta-cell differentiation by regulating beta-cell mass during development [10]. It has also been observed that embryonic dorsal root ganglia affect insulin secretion in co-cultured islets [11], that co-cultured islets and NCSCs have mutual beneficial effects in vitro [12], and that co-transplantation of NCSC-derived neurospheres with islets induces proliferation and promotes function of transplanted beta-cells [13]. "
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    • "Functioning as a trophic factor in plants, 5-HT signaled in even the most primitive nervous systems to regulate the primitive energy metabolism systems [52], [53]. Considering that pancreatic islet cells and neurons share common functions and similar ontogenies [54], it is not surprising that the serotonergic nervous system might regulate pancreatic islet function, to form an intricate energy metabolism regulatory system with the effect on hypothalamus. Our data strongly suggest that the 5-HT system is important for metabolic control, though much remains to be understood about the function of the 5-HT system in energy metabolism, including the specific roles of each of the 5-HT receptor subtypes, and the nuances of the effector pathways. "
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) describes a group of metabolic disorders characterized by defects in insulin secretion and insulin sensitivity. Insulin secretion from pancreatic β-cells is an important factor in the etiology of T2DM, though the complex regulation and mechanisms of insulin secretion from β-cells remains to be fully elucidated. High plasma levels of serotonin (5-hydroxytryptamine; 5-HT) have been reported in T2DM patients, though the potential effect on insulin secretion is unclear. However, it is known that the 5-HT receptor 2C (5-HT(2C)R) agonist, mCPP, decreases plasma insulin concentration in mice. As such, we aimed to investigate the expression of the 5-HT(2C)R in pancreatic islets of diabetic mice and the role of 5-HT(2C)R signaling in insulin secretion from pancreatic β-cells. We found that 5-HT(2C)R expression was significantly increased in pancreatic islets of db/db mice. Furthermore, treatment with a 5-HT(2C)R antagonist (SB242084) increased insulin secretion from pancreatic islets isolated from db/db mice in a dose-dependent manner, but had no effect in islets from control mice. The effect of a 5-HT(2C)R agonist (mCPP) and antagonist (SB242084) were further studied in isolated pancreatic islets from mice and Min-6 cells. We found that mCPP significantly inhibited insulin secretion in Min-6 cells and isolated islets in a dose-dependent manner, which could be reversed by SB242084 or RNA interference against 5-HT(2C)R. We also treated Min-6 cells with palmitic acid for 24 h, and found that the expression of 5-HT(2C)R increased in a dose-dependent manner; furthermore, the inhibition of insulin secretion in Min-6 cells induced by palmitic acid could be reversed by SB242084 or RNA interference against 5-HT(2C)R. Taken together, our data suggests that increased expression of 5-HT(2C)R in pancreatic β-cells might inhibit insulin secretion. This unique observation increases our understanding of T2DM and suggests new avenues for potential treatment.
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