Hedgehog signaling in pancreas development and disease

Lau, Janet; Kawahira, Hiroshi; Hebrok, Matthias

doi:10.1007/s00018-005-5357-z

Cited by 88 publications

(71 citation statements)

References 91 publications

(117 reference statements)

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“…During early development, Hh signaling blocks pancreas formation (46). Less is known about its role at later stages because the ablation of Hh signaling in mice leads to early embryonic lethality (18).…”

Section: Discussionmentioning

confidence: 99%

Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas

et al. 2007

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The transcription factor regulatory factor X (RFX)-3 regulates the expression of genes required for the growth and function of cilia. We show here that mouse RFX3 is expressed in developing and mature pancreatic endocrine cells during embryogenesis and in adults. RFX3 expression already is evident in early Ngn3-positive progenitors and is maintained in all major pancreatic endocrine cell lineages throughout their development. Primary cilia of hitherto unknown function present on these cells consequently are reduced in number and severely stunted in Rfx3 Ϫ/Ϫ mice. This ciliary abnormality is associated with a developmental defect leading to a uniquely altered cellular composition of the islets of Langerhans. Just before birth, Rfx3 Ϫ/Ϫ islets contain considerably less insulin-, glucagon-, and ghrelinproducing cells, whereas pancreatic polypeptide-positive cells are markedly increased in number. In adult mice, the defect leads to small and disorganized islets, reduced insulin production, and impaired glucose tolerance. These findings suggest that RFX3 participates in the mechanisms that govern pancreatic endocrine cell differentiation and that the presence of primary cilia on islet cells may play a key role in this process. Diabetes 56:950 -959, 2007

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Section: Discussionmentioning

confidence: 99%

Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas

et al. 2007

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“…In the developing and mature pancreas, deregulated Hh signaling results in a series of diseases, including annular pancreas, diabetes mellitus, chronic pancreatitis and pancreatic cancer (Lau et al, 2006). During the early mouse embryonic stages, Hh signaling is kept at a low level in the pancreatic anlage to ensure the correct establishment of organ boundaries, as well as tissue architecture.…”

Section: Introductionmentioning

confidence: 99%

Characterization of primary cilia and Hedgehog signaling during development of the human pancreas and in human pancreatic duct cancer cell lines

Nielsen

Møllgård

Clément

et al. 2008

Developmental Dynamics

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Hedgehog (Hh) signaling controls pancreatic development and homeostasis; aberrant Hh signaling is associated with several pancreatic diseases. Here we investigated the link between Hh signaling and primary cilia in the human developing pancreatic ducts and in cultures of human pancreatic duct adenocarcinoma cell lines, PANC-1 and CFPAC-1. We show that the onset of Hh signaling from human embryogenesis to fetal development is associated with accumulation of Hh signaling components Smo and Gli2 in duct primary cilia and a reduction of Gli3 in the duct epithelium. Smo, Ptc, and Gli2 localized to primary cilia of PANC-1 and CFPAC-1 cells, which may maintain high levels of nonstimulated Hh pathway activity. These findings indicate that primary cilia are involved in pancreatic development and postnatal tissue homeostasis.

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“…Similarly, Ptch1 is expressed in the mesenchyme adjacent to the pancreas, but expression has not been confirmed in the pancreas area of mouse embryos before embryonic day (E) 12.5 [4]. 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].…”

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 in pancreas development and disease

Cited by 88 publications

References 91 publications

Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas

Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas

Characterization of primary cilia and Hedgehog signaling during development of the human pancreas and in human pancreatic duct cancer cell lines

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

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