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

Benjamin Cyge,Eunice N Kim,Ken-Ichi Takemaru,Mohammed Hoque,Feng-Qian Li,Howard C Crawford,Randall T Moon,Vera Voronina,Gregory J Pazour,Jason Hall,Jennifer M Bailey-Lundberg

doi:10.1038/s41598-021-96597-w

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.

Highlights

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
We demonstrated that CEP164, which is mutated in human ciliopathies including nephronophthisis and B BS23,24, directly interacts with and recruits Cby[1] to the distal appendages during ciliogenesis[5]
Our results suggest that Cby[1] plays a crucial role in ciliogenesis in the pancreas and that Cby1-KO acinar cells accumulate zymogen granules (ZGs) throughout the cytoplasm due to defective exocytosis, leading to cell death and rapid exocrine pancreatic degeneration

Summary

Introduction

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. Chibby[1] (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Primary cilia are comprised of a 9 + 0 microtubule arrangement, present on a wide range of cell types, and play crucial roles in mechanosensation and intracellular signaling. Motile multicilia are comprised of a 9 + 2 structure and found on epithelial cells lining the respiratory tract, oviduct, and brain ventricles. Dysfunctional primary cilia are linked to various diseases such as polycystic kidney disease (PKD) and Bardet-Biedl syndrome (BBS) Their clinical features are variable but include situs inversus, retinal degeneration, intellectual disability, and cystic kidney, liver, and pancreas. CiBAR1 and ciBAR2 are recruited to mother centrioles and basal bodies by Cby[1] to facilitate ciliogenesis likely through regulation of membrane remodeling processes. It was reported that loss of Cby[1] causes a ciliopathy with features of Joubert syndrome[28]

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Conclusion