A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish

Ellis, Jillian L.; Evason, Kimberley; Zhang, Chang-wen; Fourman, Makenzie N.; Liu, Jiandong; Ninov, Nikolay; Delous, Marion; Vanhollebeke, Benoît; Fiddes, Ian T.; Otis, Jessica P.; Houvras, Yariv; Farber, Steven; Xu, Xiaolei; Stainier, Didier Y.R.; Yin, Chunyue

doi:10.1002/hep4.2038

Cited by 4 publications

(3 citation statements)

References 54 publications

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“…Rather, we identified biological processes previously found to be important in biliary development, repair, and cystogenesis; GO terms associated with cytoskeleton remodeling and cell matrix adhesion (30,31), namely, transforming growth factor-β (TGFβ) (32) and integrin (33) signaling, were changed (Fig. 1I and data file S2), adding further support to the idea that alterations in the extracellular matrix (ECM) (34) and cytoskeletal dynamics, in addition to induction of known cystogenic signaling signatures, promote the generation of cysts in vivo (35,36).…”

Section: Loss Of Primary Cilia Results In Tissue Remodeling To Form T...mentioning

confidence: 70%

A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

Waddell,

Yao,

Olaizola

et al. 2023

Sci. Transl. Med.

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The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35 ) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor–β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery.

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Section: Loss Of Primary Cilia Results In Tissue Remodeling To Form T...mentioning

confidence: 70%

A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

Waddell,

Yao,

Olaizola

et al. 2023

Sci. Transl. Med.

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show abstract

“…By whole genome sequencing, it was found that cyst formation in a mutant Zebrafish phenotype occurs due to missense mutations in the FURIN gene, which encodes for a proprotein convertase. This mutation causes a change in Furin protein localization and ER stress [ 44 ].…”

Section: Er Stress Response In Liver Diseasesmentioning

confidence: 99%

“…Hepatic cysts can be treated by ER stress inhibitors like 4-phenyl butyric acid or by mTOR inhibitors such as rapamycin [ 44 ]. It has also been found that polyunsaturated fatty acids (PUFA) have anti-inflammatory properties which protect liver cells from the toxicity induced by bile acids [ 118 ].…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review

Shreya,

Grosset,

Jain

2023

IJMS

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Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of UPR—IRE1 (Inositol requiring enzyme 1), PERK (Protein kinase RNA-activated (PKR)-like ER kinase), and ATF6 (Activating transcription factor 6)—modulate the gene expression pattern through increased expression of chaperones and restore ER homeostasis by enhancing ER protein folding capacity. The liver is a central organ which performs a variety of functions which help in maintaining the overall well-being of our body. The liver plays many roles in cellular physiology, blood homeostasis, and detoxification, and is the main site at which protein synthesis occurs. Disturbance in ER homeostasis is triggered by calcium level imbalance, change in redox status, viral infection, and so on. ER dysfunction and subsequent UPR signaling participate in various hepatic disorders like metabolic (dysfunction) associated fatty liver disease, liver cancer, viral hepatitis, and cholestasis. The exact role of ER stress and UPR signaling in various liver diseases is not fully understood and needs further investigation. Targeting UPR signaling with drugs is the subject of intensive research for therapeutic use in liver diseases. The present review summarizes the role of UPR signaling in liver disorders and describes why UPR regulators are promising therapeutic targets.

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A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish

et al. 2022

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Hepatic cysts are fluid-filled lesions in the liver that are estimated to occur in 5% of the population. They may cause hepatomegaly and abdominal pain.Progression to secondary fibrosis, cirrhosis, or cholangiocarcinoma can lead to morbidity and mortality. Previous studies of patients and rodent models have associated hepatic cyst formation with increased proliferation and fluid secretion in cholangiocytes, which are partially due to impaired primary cilia.Congenital hepatic cysts are thought to originate from faulty bile duct development, but the underlying mechanisms are not fully understood. In a forward genetic screen, we identified a zebrafish mutant that developed hepatic cysts

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A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish

Cited by 4 publications

References 54 publications

A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review

A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish

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