Thomas M K, Rastalsky N, Lee J H, Habener J F
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston 02114, USA.
Diabetes. 2000 Dec;49(12):2039-47. doi: 10.2337/diabetes.49.12.2039.
Hedgehogs (Hhs) are intercellular signaling molecules that regulate tissue patterning in mammalian development. Mammalian Hhs include Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). The absence of Shh expression is required for the early development of the endocrine and exocrine pancreas, but whether Hh signaling functions in the fully developed adult endocrine pancreas is unknown. Here we report that Hhs Ihh and Dhh and their receptors patched (Ptc) and smoothened are expressed in the endocrine islets of Langerhans of the fully developed rat pancreas and in the clonal gamma-cell line INS-1. We demonstrate the coexpression of Ptc with insulin in beta-cells of mouse pancreatic islets, indicating that beta-cells are targets of active Hh signaling. The administration of cyclopamine, a Hh signaling inhibitor, decreases both insulin secretion from and insulin content of INS-1 cells. The effects of Hh signaling on insulin production occur at the transcriptional level because activation of Hh signal transduction by ectopic expression of Shh increases rat insulin I promoter activation in a dose-dependent manner in transient transfections of INS-1 and MIN6 beta-cell lines. In contrast, inhibition of Hh signaling with increasing concentrations of cyclopamine progressively reduces insulin promoter activity. Furthermore, the treatment of INS-1 cells with cyclopamine diminishes endogenous insulin mRNA expression. We propose that Hh signaling is not restricted to patterning in early pancreas development but also continues to signal in differentiated beta-cells of the endocrine pancreas in regulating insulin production. Thus, defective Hh signaling in the pancreas should be considered as a potential factor in the pathogenesis of type 2 diabetes.
刺猬因子（Hhs）是调节哺乳动物发育过程中组织模式形成的细胞间信号分子。哺乳动物的刺猬因子包括音猬因子（Shh）、印度刺猬因子（Ihh）和沙漠刺猬因子（Dhh）。内分泌和外分泌胰腺的早期发育需要Shh表达缺失，但刺猬因子信号通路在完全发育的成年内分泌胰腺中是否发挥作用尚不清楚。在此，我们报告刺猬因子Ihh和Dhh及其受体patched（Ptc）和smoothened在完全发育的大鼠胰腺胰岛以及克隆的γ细胞系INS-1中表达。我们证明在小鼠胰岛的β细胞中Ptc与胰岛素共表达，表明β细胞是活跃的刺猬因子信号通路的靶点。给予刺猬因子信号通路抑制剂环杷明可降低INS-1细胞的胰岛素分泌和胰岛素含量。刺猬因子信号通路对胰岛素产生的影响发生在转录水平，因为在INS-1和MIN6β细胞系的瞬时转染中，通过异位表达Shh激活刺猬因子信号转导以剂量依赖方式增加大鼠胰岛素I启动子的活性。相反，随着环杷明浓度增加抑制刺猬因子信号通路会逐渐降低胰岛素启动子活性。此外，用环杷明处理INS-1细胞会减少内源性胰岛素mRNA表达。我们提出，刺猬因子信号通路不仅限于胰腺早期发育的模式形成，而且在调节胰岛素产生的过程中，在分化的内分泌胰腺β细胞中持续发挥信号作用。因此，胰腺中刺猬因子信号通路缺陷应被视为2型糖尿病发病机制中的一个潜在因素。
