Hedgehog signaling regulation of insulin production by pancreatic beta-cells.

Thomas, Melissa K.; Rastalsky, Naina; Lee, Jee H.; Habener, Joel F.

doi:10.2337/diabetes.49.12.2039

Cited by 143 publications

(146 citation statements)

References 60 publications

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“…To determine the consequences of blocking this pathway, cells were treated with cyclopamine, a known inhibitor of Hh signalling. Treatments were carried out using 5, 10 and 20 M cyclopamine (doses previously described 14,21 ) to determine whether this inhibition reduced cell growth and induced apoptotic cell death.…”

Section: Cyclopamine Treatment Results In Reduced Cell Yield and Incrmentioning

confidence: 99%

“…20 Cyclopamine treatments were carried out using DMEM-F12 (Invitrogen, Paisley, UK) supplemented with 2% FBS, and the doses were previously described. 14,21 Cells (2 ϫ 10 6 /flask) were seeded in triplicate flasks and allowed to grow to approximately 50% confluence prior to treatment. Cells were treated for 48 hr and trypsinized for counting and analysis.…”

Section: Treatment With Cyclopaminementioning

confidence: 99%

See 1 more Smart Citation

Hedgehog signalling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment

Qualtrough

Buda

Gaffield

et al. 2004

Intl Journal of Cancer

153

138

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Section: Cyclopamine Treatment Results In Reduced Cell Yield and Incrmentioning

confidence: 99%

Section: Treatment With Cyclopaminementioning

confidence: 99%

Hedgehog signalling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment

Qualtrough

Buda

Gaffield

et al. 2004

Intl Journal of Cancer

153

138

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“…In this regard, in studies of Pdx1−/− mice, the initial buds of the pancreas form but subsequent branching and morphogenesis of these buds is arrested [12]. By contrast, in the mature pancreas and related islet-derived cell lines, ongoing expression of hedgehog proteins appear to be important for the maintenance of both Pdx1 and insulin expression [32,33]. These findings suggest a complex interplay between hedgehog proteins and Pdx1 expression, and that regulation of Pdx1 gene expression appears to be differentially regulated in the developing pancreas vs. the mature pancreas.…”

Section: Pdx1 and Early Pancreas Developmentmentioning

confidence: 99%

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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“…Thereafter, the developing tissue starts to express several HH components [7,8]. The expression of Ptch1 has been confirmed by RT-PCR assay after E13.5, and mature pancreas expresses Ihh, Dhh, Hhip, Ptch1 and Smo in islet and ductal cells [8][9][10][11]. Several groups have investigated the effect of increased HH signalling on pancreatic morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

et al. 2008

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Aims/hypothesis Ectopic activation of hedgehog (HH) signalling in pancreas induces various abnormal morphogenetic events in the pancreas. This study analysed the dose-dependent requirement of patched homologue 1 (PTCH1), a negative regulator of HH signalling on pancreatic development. Methods We used a recessive spontaneous mutant mouse denoted as mes which carries a mutated Ptch1 resulting in deletion of the most carboxy-terminal cytoplasmic domain of the PTCH1 protein. In this study, we analysed pancreatic morphology in Ptch1 +/+ , Ptch1 +/mes , Ptch1 +/− , Ptch1 mes/mes and Ptch1 −/mes mouse embryos, as well as the islet mass in adult Ptch1 +/+ , Ptch1 +/mes and Ptch1 +/− mice. Results Until embryonic day (E) 12.5, no obvious abnormality of pancreas was observed in any of the Ptch1 mutants. The levels of PDX1 and glucagon were also not evidently different among the mice genotypes studied. Thereafter, morphological abnormalities appeared in the Ptch1 mutant mice. The beta, alpha and exocrine cell masses decreased at E18.5 in parallel with increased HH signalling, with beta cell mass showing the highest sensitivity to HH signalling with a significant decrease even in Ptch1 +/mes mice. Adult Ptch1 +/− mice also showed a significant decrease in beta cell mass compared with wild-type mice. Conclusions/interpretation Our findings indicate that the carboxy-terminal domain of Ptch1 is essential for pancreatic development. In addition, the loss of Ptch1 function decreases both the endocrine and exocrine cell mass in a dose-dependent manner, with beta cells particularly sensitive to changes in HH signalling.

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Hedgehog signaling regulation of insulin production by pancreatic beta-cells.

Cited by 143 publications

References 60 publications

Hedgehog signalling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment

Hedgehog signalling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

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