Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm

Menezes, Luís F.; Cai, Yiqiang; Nagasawa, Yasuyuki; Silva, Ana M. G.; Watkins, Mary L.; Silva, da; Somlo, Stefan; Guay‐Woodford, Lisa M.; Germino, Gregory G.; Onuchic, Luiz Fernando

doi:10.1111/j.1523-1755.2004.00844.x

Cited by 147 publications

(151 citation statements)

References 41 publications

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“…Although the gene responsible for ARPKD, PKHD1, has been identified [23][24][25] and its gene product, FPC, has been initially characterized, 27,28,30,31,39,40 the mechanisms by which PKHD1 causes disease phenotypes remain largely unknown. To study the disease mechanism and pathogenesis of ARPKD, we created a mouse that allows manipulation of Pkhd1, an animal model that recapitulates the human ARPKD phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…FPC was demonstrated to localize to the primary cilium and/or basal bodies of renal tubular epithelia, [27][28][29][30][31] and malformation of the cilia was shown to induce cyst formation in the kidneys 34,35 ; therefore, we began to determine whether the lack of FPC also disrupts ciliogenesis in Pkhd1-deficient mice. We used IF with an anti-acetylated ␣-tubulin antibody to examine the number and morphology of renal primary cilia in 6-moold littermates.…”

Section: Lack Of Fpc Exhibits Aberrant Ciliogenesis In the Renal Epitmentioning

confidence: 99%

“…The longest open reading frame is predicted to include 66 exons and to encode the 4074 -amino acid membrane-associated receptor-like protein fibrocystin/polyductin (FPC). [23][24][25][26] It was shown that FPC is associated with the basal bodies/primary cilia of epithelial cells [27][28][29][30] and co-localizes with PC2 within the cell. 31 These observations suggest the possibility that FPC and PC2 may function in a common molecular pathway in vivo.…”

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confidence: 99%

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Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

129

105

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Autosomal recessive polycystic kidney disease is caused by mutations in PKHD1, which encodes the membrane-associated receptor-like protein fibrocystin/polyductin (FPC). FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway. For investigation of this, a mouse model with a gene-targeted mutation in Pkhd1 that recapitulates phenotypic characteristics of human autosomal recessive polycystic kidney disease was produced. The absence of FPC is associated with aberrant ciliogenesis in the kidneys of Pkhd1-deficient mice. It was found that the COOH-terminus of FPC and the NH2-terminus of PC2 interact and that lack of FPC reduced PC2 expression but not vice versa, suggesting that PC2 may function immediately downstream of FPC in vivo. PC2-channel activities were dysregulated in cultured renal epithelial cells derived from Pkhd1 mutant mice, further supporting that both cystoproteins function in a common pathway. In addition, mice with mutations in both Pkhd1 and Pkd2 had a more severe renal cystic phenotype than mice with single mutations, suggesting that FPC acts as a genetic modifier for disease severity in autosomal dominant polycystic kidney disease that results from Pkd2 mutations. It is concluded that a functional and molecular interaction exists between FPC and PC2 in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Lack Of Fpc Exhibits Aberrant Ciliogenesis In the Renal Epitmentioning

confidence: 99%

mentioning

confidence: 99%

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Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

129

105

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“…When these genes are mutated, the absence of their protein products results in ciliary dysfunction and cyst formation. [6][7][8][9][10][11] Development of cysts in the liver is the most frequent extra-renal manifestation in both ADPKD and ARPKD. 10-13 Although in ADPKD the liver generally functions normally, the progressive increase in size of the polycystic liver causes abdominal pain, early postprandial fullness and/or shortness of breath, and thus significantly affects quality of life.…”

Section: Introductionmentioning

confidence: 99%

Cholangiocyte Cilia Detect Changes in Luminal Fluid Flow and Transmit Them Into Intracellular Ca2+ and cAMP Signaling

et al. 2006

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Background & Aims-Each cholangiocte in the biliary tree has a primary cilium extending from the apical plasma membrane into the ductal lumen. While the physiological significance of cholangiocyte cilia is unknown, studies in renal epithelia suggest that primary cilia possess sensory functions. Here, we tested the hypothesis that cholangiocyte cilia are sensory organelles that detect and transmit luminal bile flow stimuli into intracellular Ca 2+ ([Ca 2+ ] i ) and cAMP signaling.

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“…Some of the PKD proteins are also localized to the basal body. [66][67][68]88 Since centrioles are the defining unit of both basal bodies and centrosomes, malfunction of proteins associated with centrioles could interfere with their centrosomal function and lead to alterations in the cell cycle and cell proliferation. 2,9,89,90 We know that disruption in the function of the PKD proteins can lead to aberrant regulation of cell proliferation/apoptosis in developing and adult tissues (reviewed in Boletta and Germino 51 ), but what is the function of flow-regulated polycystin 1 and polycystin 2 signaling in a normal kidney?…”

Section: Cilia-related Disorders J Pan Et Almentioning

confidence: 99%

Cilium-generated signaling and cilia-related disorders

Pan

Wang

Snell

2005

Laboratory Investigation

211

183

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Biologists have long known that humans experience their environment through cilia. Light, odorant, and sound perception depend on these microtubule-filled, complex organelles present on cells in primary sensory tissues. Recently, discoveries on the mechanism of assembly of cilia (flagella) in the lowly, biflagellated, eucaryotic green alga Chlamydomonas have triggered a renaissance of interest in the organelles along with a recognition of their key sensory roles in nonsensory tissues. Chlamydomonas researchers uncovered an entirely new set of cellular machinery essential for transporting the protein components of cilia and flagella in all ciliated/ flagellated eukaryotic cells between their site of synthesis in the cell body and their site of assembly at the tip of the flagellum (intraflagellar transport: IFT). Prompted by the surprising observations that disruption of IFT genes in mice led to polycystic kidney disease (PKD) and that PKD proteins are present on the sensory cilia of Caenorhabditis elegans, researchers have made a direct connection between PKD and cilia. At least five (and possibly all) of the seven identified human genes disrupted in PKD and a related disorder nephronophthisis encode proteins expressed in the primary cilia that project into the lumen from the epithelial cells that line renal tubules. Moreover, the renal cilia are flow sensors and at least two of the PKD genes encode ciliary transmembrane proteins essential for mechanosensation. Although their roles have not yet been as clearly identified, cilia also are at the center of a rare human disorder, Bardet-Biedl syndrome (BBS), in which patients exhibit phenotypes of common human diseases, including obesity and increased incidence of hypertension and diabetes. Five of the eight known BBS genes encode basal body or cilia proteins in mice or humans, and homologues of two of the remaining genes are present in basal bodies/cilia of model organisms. Here we briefly describe the biology of cilia and flagella, we outline how studies on model organisms have led to our current understanding of the roles of these organelles and their proteins in health and disease, and we highlight the notion that the primary cilia present on cells throughout the body, even those on brain neurons, may be essential for as yet undiscovered cilium-generated signaling functions.

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Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm

Cited by 147 publications

References 41 publications

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Cholangiocyte Cilia Detect Changes in Luminal Fluid Flow and Transmit Them Into Intracellular Ca2+ and cAMP Signaling

Cilium-generated signaling and cilia-related disorders

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