Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

Abstract

While relatively ignored for years as vestigial, cilia have recently become the focus of intense interest as organelles that result in severe pathologies when disrupted. Here, we further establish a connection between cilia dysfunction and disease by showing that loss of polaris (Tg737), an intraflagellar transport (IFT) protein required for ciliogenesis, causes abnormalities in the exocrine and endocrine pancreas of the Tg737 orpk mouse. Pathology is evident late in gestation as dilatations of the pancreatic ducts that continue to expand postnatally. Shortly after birth, the acini become disorganized, undergo apoptosis, and are largely ablated in late stage pathology. In addition, serum amylase levels are elevated and carboxypeptidase is abnormally activated within the pancreas. Ultrastructural analysis reveals that the acini undergo extensive vacuolization and have numerous 'halo-granules' similar to that seen in induced models of pancreatitis resulting from duct obstruction. Intriguingly, although the acini are severely affected in Tg737 orpk mutants, cilia and Tg737 expression are restricted to the ducts and islets and are not detected on acinar cells. Analysis of the endocrine pancreas in Tg737 orpk mutants revealed normal differentiation and distribution of cell types in the islets. However, after fasting, mutant blood glucose levels are significantly lower than controls and when challenged in glucose tolerance tests, Tg737 orpk mutants exhibited defects in glucose uptake. These findings are interesting in light of the recently proposed role for polaris, the protein encoded by the Tg737 gene, in the hedgehog pathway and hedgehog signaling in insulin production and glucose homeostasis.

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

“…However, Foxa2 is known to be implicated in the development and function of pancreatic endocrine cells (43). Second, mice carrying a hypomorphic allele of the Ift88 gene-the second RFX3 target gene that is downregulated in Rfx3 Ϫ/Ϫ mice-are hypoglycemic after fasting and show a marked delay in return to baseline blood glucose levels after glucose challenge (30). This altered glucose homeostasis could result from deficient glucagon and insulin production, although no overt islet defects were documented (30).…”

“…Second, mice carrying a hypomorphic allele of the Ift88 gene-the second RFX3 target gene that is downregulated in Rfx3 Ϫ/Ϫ mice-are hypoglycemic after fasting and show a marked delay in return to baseline blood glucose levels after glucose challenge (30). This altered glucose homeostasis could result from deficient glucagon and insulin production, although no overt islet defects were documented (30). Third, the transcription factor Hnf6 has been implicated in both endocrine cell differentiation and the regulation of primary cilia formation in the pancreas (44,45).…”

“…diseases and animal models, the pathology frequently extends to other systems, particularly the liver and pancreas, suggesting that primary cilia play key roles in these organs as well (11,(27)(28)(29)(30).…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Accumulating evidence from several groups indicate that the primary cilia found on most vertebrate cells have an important but undefined role in the Hh pathway (Huangfu et al, 2003;Corbit et al, 2005;Huangfu and Anderson, 2005;May et al, 2005;Zhang et al, 2005;Hoover et al, 2008). Functions of primary cilium is regulated by large protein complexes involved in intraflagellar transport (IFT), which functions in retrograde and anterograde movement of cargo within the primary cilia (Scholey and Anderson, 2006).…”

Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease

“…Whether these pathologies are caused by cilia-mediated signaling defects remains to be fully explored; however, this seems likely in light of the systemic nature of the disease seen in the Tg737 orpk hypomorphic mutant (6,79). The partial loss of IFT and cilia function in these mice results in cyst formation in the liver along with bile duct hyperplasia and severe pancreatic defects (80,81).…”