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...

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Autores principales: Benjamin Cyge, Vera Voronina, Mohammed Hoque, Eunice N. Kim, Jason Hall, Jennifer M. Bailey-Lundberg, Gregory J. Pazour, Howard C. Crawford, Randall T. Moon, Feng-Qian Li, Ken-Ichi Takemaru
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Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/887b15da67ff49449b0c627a4c5d0c9c
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spelling oai:doaj.org-article:887b15da67ff49449b0c627a4c5d0c9c2021-12-02T19:02:23ZLoss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis10.1038/s41598-021-96597-w2045-2322https://doaj.org/article/887b15da67ff49449b0c627a4c5d0c9c2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96597-whttps://doaj.org/toc/2045-2322Abstract 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.Benjamin CygeVera VoroninaMohammed HoqueEunice N. KimJason HallJennifer M. Bailey-LundbergGregory J. PazourHoward C. CrawfordRandall T. MoonFeng-Qian LiKen-Ichi TakemaruNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Benjamin Cyge
Vera Voronina
Mohammed Hoque
Eunice N. Kim
Jason Hall
Jennifer M. Bailey-Lundberg
Gregory J. Pazour
Howard C. Crawford
Randall T. Moon
Feng-Qian Li
Ken-Ichi Takemaru
Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis
description 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.
format article
author Benjamin Cyge
Vera Voronina
Mohammed Hoque
Eunice N. Kim
Jason Hall
Jennifer M. Bailey-Lundberg
Gregory J. Pazour
Howard C. Crawford
Randall T. Moon
Feng-Qian Li
Ken-Ichi Takemaru
author_facet Benjamin Cyge
Vera Voronina
Mohammed Hoque
Eunice N. Kim
Jason Hall
Jennifer M. Bailey-Lundberg
Gregory J. Pazour
Howard C. Crawford
Randall T. Moon
Feng-Qian Li
Ken-Ichi Takemaru
author_sort Benjamin Cyge
title Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis
title_short Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis
title_full Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis
title_fullStr Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis
title_full_unstemmed Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis
title_sort loss of the ciliary protein chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/887b15da67ff49449b0c627a4c5d0c9c
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