Defects in Cholangiocyte Fibrocystin Expression and Ciliary Structure in the PCK Rat

Tatyana V. Masyuk, Bing Q. Huang, Christopher J. Ward, Anatoliy I. Masyuk, David Yuan, Patrick L. Splinter, Rachaneekorn Punyashthiti, Eric L. Ritman, Vicente Torres, Peter C Harris, Nicholas F La Russo

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

Background & Aims: Recent studies have showed that proteins associated with polycystic kidney disease (PKD) are expressed in cilia, linking this organelle and cyst formation in the kidney, but involvement of cilia in PKD-related biliary cystogenesis has not been shown. We investigated: (1) the expression of fibrocystin (a product of PKHD1, the autosomal-recessive PKD [ARPKD] gene) in cholangiocyte cilia; (2) biliary cyst formation in an orthologous rat model, PCK; and (3) the effect of Pkhdl mutation on ciliary structure. Methods: Biliary cystogenesis was assessed by microcomputed tomography. Fibrocystin expression in cholangiocytes of isolated intrahepatic bile ducts (IBDUs) and liver cysts was analyzed by confocal and immunoelectron microscopy, and ciliary structure and length by scanning and transmission electron microscopy. Small interfering RNAs (siRNA) were used to examine the effect of fibrocystin loss on ciliary structure. Results: The biliary tree in the PCK rat was distorted markedly, showing multiple bile duct dilatation and focal budding. In normal IBDUs, each cholangiocyte had a single cilium that expressed fibrocystin. In contrast, cilia in the PCK rat were abnormal with bulbous extensions and diminished length, and were devoid of fibrocystin. In cholangiocytes of normal IBDUs, specific siRNA reduced Pkhdl messenger RNA by 80%, the length of cilia by 41%, and fibrocystin ciliary expression to an undetectable level. Conclusions: Our results indicate that fibrocystin is expressed in cholangiocyte cilia and that disruption of Pkhdl by a germ line mutation in the PCK rat or by siRNA in IBDUs results in abnormalities in ciliary morphology and possibly biliary cystogenesis.

Original languageEnglish (US)
Pages (from-to)1303-1310
Number of pages8
JournalGastroenterology
Volume125
Issue number5
DOIs
StatePublished - Nov 2003

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Cilia
Intrahepatic Bile Ducts
Small Interfering RNA
Polycystic Kidney Diseases
Cysts
Autosomal Recessive Polycystic Kidney
Choledochal Cyst
X-Ray Microtomography
Scanning Transmission Electron Microscopy
Immunoelectron Microscopy
Germ-Line Mutation
Biliary Tract
Bile Ducts
Confocal Microscopy
Organelles
Dilatation
Kidney
Messenger RNA
Mutation
Liver

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Masyuk, T. V., Huang, B. Q., Ward, C. J., Masyuk, A. I., Yuan, D., Splinter, P. L., ... La Russo, N. F. (2003). Defects in Cholangiocyte Fibrocystin Expression and Ciliary Structure in the PCK Rat. Gastroenterology, 125(5), 1303-1310. https://doi.org/10.1016/j.gastro.2003.09.001

Defects in Cholangiocyte Fibrocystin Expression and Ciliary Structure in the PCK Rat. / Masyuk, Tatyana V.; Huang, Bing Q.; Ward, Christopher J.; Masyuk, Anatoliy I.; Yuan, David; Splinter, Patrick L.; Punyashthiti, Rachaneekorn; Ritman, Eric L.; Torres, Vicente; Harris, Peter C; La Russo, Nicholas F.

In: Gastroenterology, Vol. 125, No. 5, 11.2003, p. 1303-1310.

Research output: Contribution to journalArticle

Masyuk, TV, Huang, BQ, Ward, CJ, Masyuk, AI, Yuan, D, Splinter, PL, Punyashthiti, R, Ritman, EL, Torres, V, Harris, PC & La Russo, NF 2003, 'Defects in Cholangiocyte Fibrocystin Expression and Ciliary Structure in the PCK Rat', Gastroenterology, vol. 125, no. 5, pp. 1303-1310. https://doi.org/10.1016/j.gastro.2003.09.001
Masyuk TV, Huang BQ, Ward CJ, Masyuk AI, Yuan D, Splinter PL et al. Defects in Cholangiocyte Fibrocystin Expression and Ciliary Structure in the PCK Rat. Gastroenterology. 2003 Nov;125(5):1303-1310. https://doi.org/10.1016/j.gastro.2003.09.001
Masyuk, Tatyana V. ; Huang, Bing Q. ; Ward, Christopher J. ; Masyuk, Anatoliy I. ; Yuan, David ; Splinter, Patrick L. ; Punyashthiti, Rachaneekorn ; Ritman, Eric L. ; Torres, Vicente ; Harris, Peter C ; La Russo, Nicholas F. / Defects in Cholangiocyte Fibrocystin Expression and Ciliary Structure in the PCK Rat. In: Gastroenterology. 2003 ; Vol. 125, No. 5. pp. 1303-1310.
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AU - Masyuk, Tatyana V.

AU - Huang, Bing Q.

AU - Ward, Christopher J.

AU - Masyuk, Anatoliy I.

AU - Yuan, David

AU - Splinter, Patrick L.

AU - Punyashthiti, Rachaneekorn

AU - Ritman, Eric L.

AU - Torres, Vicente

AU - Harris, Peter C

AU - La Russo, Nicholas F

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AB - Background & Aims: Recent studies have showed that proteins associated with polycystic kidney disease (PKD) are expressed in cilia, linking this organelle and cyst formation in the kidney, but involvement of cilia in PKD-related biliary cystogenesis has not been shown. We investigated: (1) the expression of fibrocystin (a product of PKHD1, the autosomal-recessive PKD [ARPKD] gene) in cholangiocyte cilia; (2) biliary cyst formation in an orthologous rat model, PCK; and (3) the effect of Pkhdl mutation on ciliary structure. Methods: Biliary cystogenesis was assessed by microcomputed tomography. Fibrocystin expression in cholangiocytes of isolated intrahepatic bile ducts (IBDUs) and liver cysts was analyzed by confocal and immunoelectron microscopy, and ciliary structure and length by scanning and transmission electron microscopy. Small interfering RNAs (siRNA) were used to examine the effect of fibrocystin loss on ciliary structure. Results: The biliary tree in the PCK rat was distorted markedly, showing multiple bile duct dilatation and focal budding. In normal IBDUs, each cholangiocyte had a single cilium that expressed fibrocystin. In contrast, cilia in the PCK rat were abnormal with bulbous extensions and diminished length, and were devoid of fibrocystin. In cholangiocytes of normal IBDUs, specific siRNA reduced Pkhdl messenger RNA by 80%, the length of cilia by 41%, and fibrocystin ciliary expression to an undetectable level. Conclusions: Our results indicate that fibrocystin is expressed in cholangiocyte cilia and that disruption of Pkhdl by a germ line mutation in the PCK rat or by siRNA in IBDUs results in abnormalities in ciliary morphology and possibly biliary cystogenesis.

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