Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis

Abstract

Primary cilia protrude from the apical surface of many cell types and act as a sensory organelle that regulates diverse biological processes ranging from chemo- and mechanosensation to signaling. Ciliary dysfunction is associated with a wide array of genetic disorders, known as ciliopathies. Polycystic lesions are commonly found in the kidney, liver, and pancreas of ciliopathy patients and mouse models. However, the pathogenesis of the pancreatic phenotype remains poorly understood. Chibby1 (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Here, we report that Cby1-knockout (KO) mice develop severe exocrine pancreatic atrophy with dilated ducts during early postnatal development. A significant reduction in the number and length of cilia was observed in Cby1-KO pancreta. In the adult Cby1-KO pancreas, inflammatory cell infiltration and fibrosis were noticeable. Intriguingly, Cby1-KO acinar cells showed an accumulation of zymogen granules (ZGs) with altered polarity. Moreover, isolated acini from Cby1-KO pancreas exhibited defective ZG secretion in vitro. Collectively, our results suggest that, upon loss of Cby1, concomitant with ciliary defects, acinar cells accumulate ZGs due to defective exocytosis, leading to cell death and progressive exocrine pancreatic degeneration after birth.

Rediscovering Primary Cilia in Pancreatic Islets

“…The global Ift88 homozygous mutant mice present with absent or shortened pancreatic cilia, which in the pancreas exhibits as reduced pancreas mass with collagen deposition, progressive acinar cell loss, and ductal hyperplasia with pancreatic cyst formation [ 16 ]. These exocrine defects are consistent with phenotypes seen in knockout mouse models of ciliary protein Chibby1 or pancreas-specific kinesin family member 3A ( Kif3a ), an essential gene for cilia formation [ 43 , 72 ]. Proposed mechanisms for these pancreatic morphological changes include defective exocytosis of zymogen granules, intrapancreatic activation of digestive enzymes such as carboxypeptidase, and activation of transforming growth factor β and mitogen-activated protein kinase kinase/extracellular signal-regulating kinase pathways [ 41 , 43 , 72 ].…”

“…In humans, primary cilia in the pancreas were first reported in β-cell tumor cells in 1964 [ 45 ]. So far, in human islets, only β- and α-cells have been documented to have primary cilia [ 42 , 45 ], whereas in the exocrine pancreas, primary cilia have been identified on ductal and centroacinar cells in both human and mouse [ 16 , 27 , 29 , 43 ]. RNA sequencing studies have demonstrated robust expression of cilia-related genes across cell types in mouse and human pancreas and islets, whose expressions are dynamically modulated by metabolic conditions such as hyperglycemia and diabetes mellitus [ 46 - 49 ].…”

“…Primary cilia are dynamic organelles whose assembly and disassembly are linked to the cell cycle and differentiation status of the cell [ 69 - 71 ]. The role of primary cilia in pancreas development has been studied using genetic mouse models targeting ciliogenesis or cilia function ( Table 2 ) [ 16 , 40 - 43 , 54 , 72 - 81 ]. The global Ift88 homozygous mutant mice present with absent or shortened pancreatic cilia, which in the pancreas exhibits as reduced pancreas mass with collagen deposition, progressive acinar cell loss, and ductal hyperplasia with pancreatic cyst formation [ 16 ].…”

Murine Chronic Pancreatitis Model Induced by Partial Ligation of the Pancreatic Duct Encapsulates the Profile of Macrophage in Human Chronic Pancreatitis

“…We considered that 21d was the time point when CP injury was the severest in our study based on Demols criteria. Interestingly, the pancreatic parenchyma was replaced by a large amount of adipose tissue at 28d after surgery, namely lipomatosis (26). In order to verify the correlation between the mouse CP model constructed by pancreatic duct ligation and human CP, we collected three clinical samples of patients with CP caused by obstructive etiologies and three normal pancreatic samples for research.…”

“…Masson and Sirius red staining showed that fibrosis appeared from 7d, peaked on 21d, and still existed at 28d. However, due to lipomatosis (26), the fibrotic area decreased compared with that at 21d (Figures 3A, H). We collected some pancreatic tissues from clinical CP patients with a background of obstructive etiologies and human nonmalignant pancreatic patients for the HE, Masson and Sirius red staining, which exhibited obvious fibrosis and parenchymal loss (Figure 3B), and the percentage of fibrosis area in human CP specimen was closer to that at 21d in mice (Figures 3H, I).…”