Primary Cilia Deletion in Pancreatic Epithelial Cells Results in Cyst Formation and Pancreatitis

Cano, David A.; Sekine, Shigeki; Hebrok, Matthias

doi:10.1053/j.gastro.2006.10.050

Cited by 121 publications

(122 citation statements)

References 68 publications

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“…Thus, it is likely that SSTR3 on the primary cilia may regulate insulin secretion and other B cell functions via a unique mechanism which differs from the reception of somatostatin on the cell body of B cells. This idea accords with a finding that a genetic deletion of the primary cilia with inactivated Kif3a in the whole pancreas induced severe dilation of the duct system in the exocrine pancreas but did not affect basic islet formation (arrangement of A and B cells) and functions (glucose tolerance tests) (5). Since a cell line of murine insulin cells (MIN6) consistently possessed the primary cilia expressing SSTR3, the precise function of the primary cilia in B cells may be verified in future studies by cell-biological methods including a controlled formation of cilia.…”

Section: Discussionsupporting

confidence: 90%

“…Therefore, an interesting inquiry to be addressed in future studies is whether BBS patients and BBS protein-knockout mice normally express SSTR3 on the primary cilia of insulin cells. Cells of pancreatic ducts and islets possess the primary cilia, but acinar cells of the exocrine pancreas apparently lack them (1,5,22,39). An electron microscopic study by Yamamoto and Kataoka (39) has reported in detail the ultrastructure of primary cilia on islet cells of some animal species.…”

Section: Discussionmentioning

confidence: 99%

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Restricted expression of somatostatin receptor 3 to primary cilia in the pancreatic islets and adenohypophysis of mice

2011

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The primary cilium is now considered to function as a fundamental, not rudimentary, structure for mechanical and chemical sensing by individual cells. Primary cilia in neurons express type III adenylyl cyclase (ACIII) and GPCRs for somatostatin (somatostatin receptor 3, SSTR3), serotonin, and melanin-concentrating hormone. The present immunohistochemical and electron microscopic study revealed an abundant occurrence of SSTR3-expressing solitary cilia in insulin-and growth hormone-secreting cells of the mouse. The SSTR3 immunoreactivity was restricted to the plasma membrane of cilia in both cell types, differing from previously reported immunohistochemical localization of SSTRs to cell bodies. The primary cilia in the islet cells were longer than those in the pituitary cells and extended for a long distance in the intercellular canalicules endowed with microvilli. No other endocrine organs were provided with the SSTR3-expressing primary cilia, while the primary cilia in these organs were frequently immunolabeled with ACIII antibody. Since the somatostatin inhibition of both insulin and GH release is regulated mainly by SSTR1 and SSTR5, the primary cilia expressing SSTR3 may be involved in a signaling which differs from that via other SSTR subtypes expressing in cell bodies.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Restricted expression of somatostatin receptor 3 to primary cilia in the pancreatic islets and adenohypophysis of mice

2011

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“…No pancreatic endocrine phenotype was observed in conditional knockout mice in which cilia formation was perturbed in the pancreas by inducing deletion of the Kif3a gene with a Pdx-cre transgene (41). This raises the possibility that the islet phenotype observed in Rfx3 Ϫ/Ϫ mice might be because of a mechanism that is independent of cilia.…”

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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“…This may indicate a functional similarity between cilia in kidney and pancreatic duct systems. Cells of both exocrine and endocrine systems in the pancreas possess primary cilia, including islet cells and the ducts, but apparently not the acini (Kodama, 1983;Ashizawa et al, 1997;Cano et al, 2004Cano et al, , 2006Zhang et al, 2005). Pancreas abnormalities in the Tg737 orpk mouse begin with dilations of the pancreas ducts in late gestation, which after birth are accompanied by extensive formation of large, interconnected cysts as well as apoptosis and vacuolization of acini.…”

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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Primary Cilia Deletion in Pancreatic Epithelial Cells Results in Cyst Formation and Pancreatitis

Cited by 121 publications

References 68 publications

Restricted expression of somatostatin receptor 3 to primary cilia in the pancreatic islets and adenohypophysis of mice

Restricted expression of somatostatin receptor 3 to primary cilia in the pancreatic islets and adenohypophysis of mice

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

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