Col2-Cre recombinase is co-expressed with endogenous type II collagen in embryonic renal epithelium and drives development of polycystic kidney disease following inactivation of ciliary genes

Kolpakova-Hart, Elona; Nicolae, Claudia M.; Zhou, Jing; Olsen, Bjørn R.

doi:10.1016/j.matbio.2008.05.002

Cited by 27 publications

(23 citation statements)

References 29 publications

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“…Our finding that pkd1a/b knockdown results in pleiotropic defects in the kidney, cartilage and brain are consistent with knockout models of polycystin1 in the mouse. In addition to cystic kidneys, we observe cartilage defects similar to the undulating spinal chord and short jaw phenotypes that have been reported in mouse Pkd1 knockouts (Boulter et al, 2001;Kolpakova-Hart et al, 2008). Expression of Pkd1 in the mouse is observed in the notochord and floor plate, as well as in other chondrogenic tissues (Boulter et al, 2001), similar to what we observe in zebrafish.…”

Section: Discussionsupporting

confidence: 86%

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

Mangos

Lam

Zhao

et al. 2010

Disease Models &Amp; Mechanisms

136

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SUMMARYMutations in polycystin1 (PKD1) account for the majority of autosomal dominant polycystic kidney disease (ADPKD). PKD1 mutations are also associated with vascular aneurysm and abdominal wall hernia, suggesting a role for polycystin1 in extracellular matrix (ECM) integrity. In zebrafish, combined knockdown of the PKD1 paralogs pkd1a and pkd1b resulted in dorsal axis curvature, hydrocephalus, cartilage and craniofacial defects, and pronephric cyst formation at low frequency (10-15%). Dorsal axis curvature was identical to the axis defects observed in pkd2 knockdown embryos. Combined pkd1a/b, pkd2 knockdown demonstrated that these genes interact in axial morphogenesis. Dorsal axis curvature was linked to notochord collagen overexpression and could be reversed by knockdown of col2a1 mRNA or chemical inhibition of collagen crosslinking. pkd1a/b-and pkd2-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of pkd1a/b also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with wortmannin or LY-29400 also exhibited dysregulation of col2a1 expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. Our results suggest that pkd1a/b and pkd2 interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.

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Section: Discussionsupporting

confidence: 86%

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

Mangos

Lam

Zhao

et al. 2010

Disease Models &Amp; Mechanisms

136

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“…PC1 is expressed in cells within the osteoblast lineage (18), and skeletal abnormalities have been reported in Pkd1 mutant mouse models (14,15,17,18), but from these generalized lossof-function observations it was not clear if the observed skeletal abnormalities were an indirect consequence of loss of PC1 in multiple tissues or a direct effect of loss of PC1 in osteoblasts. In the present studies, we have addressed this question by using mice had a ϳ25% reduction in Pkd1 expression, whereas Pkd1 flox/m1Bei mice had a 50% reduction but had identical effects on bone, suggests that loss of Pkd1 function in osteoblasts is responsible for the observed reduction in bone mass in both models.…”

Section: Discussionmentioning

confidence: 99%

Conditional Disruption of Pkd1 in Osteoblasts Results in Osteopenia Due to Direct Impairment of Bone Formation

Xiao

Zhang

Cao

et al. 2010

Journal of Biological Chemistry

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PC1 (polycystin-1) is a highly conserved, receptor-like multidomain membrane protein widely expressed in various cell types and tissues (1, 2). Mutations of human PKD1 (polycystic kidney disease gene 1) cause autosomal dominant polycystic kidney disease (ADPKD) 2 (3, 4). The genetics of ADPKD is complex, because it is widely held that inactivation of the normal copy of the PKD1 gene by a second somatic mutation in conjunction with the inherited mutation of the other allele is required for renal cyst formation, which occurs in only a subset of the dually affected tubules (5). Although primarily affecting the kidney, ADPKD is also a multisystem disorder (6, 7). Extrarenal manifestations include intracranial and aortic aneurysms and cystic disease of liver and pancreas (8 -11). The biological functions of PC1 are poorly defined in some tissues that express PKD1 transcripts, such as bone. Indeed, the absence of clinically demonstrable skeletal abnormalities in patients with ADPKD initially delayed the investigation of PKD1 function in bone. The apparent lack of abnormalities in other tissues expressing PC1 may arise because of differences in the frequency of a second hit somatic mutation, the presence of other modifying factors that may compensate for lack of PC1 function in other organs (12), or failure to detect more subtle phenotypes. For example, lung was not thought to be affected by PKD1 mutations until computed tomography scans of lungs of ADPKD patients showed a 3-fold increase in the prevalence of bronchiectasis compared with controls (13).Pkd1 is highly expressed in bone, and several mouse models with inactivating mutations of Pkd1 have skeletal abnormalities in the setting of polycystic kidney disease and embryonic lethality (6, 7, 14 -16). Most recently, however, the heterozygous Pkd1 m1Bei mouse, which has an inactivating mutation of Pkd1 and survives to adulthood without polycystic kidney disease, has been shown to develop osteopenia and impaired osteoblastic differentiation (17,18), suggesting that Pkd1 may function in bone. Because homozygous PKD1/Pkd1 mutations in humans and mice are lethal, and most of the existing models are globally Pkd1-deficient, the significance of inactivation of Pkd1 in osteoblasts remains uncertain, and the bone changes might reflect an indirect effect due to loss of PKD1, in the kidney or other tissues.In the current study, to determine if PKD1 in osteoblasts has a direct function in regulating postnatal skeletal functions, we used mouse genetic approaches to conditionally delete Pkd1 in osteoblasts. We demonstrate that conditional deletion of Pkd1 from osteoblasts using Oc-Cre results defective osteoblast function in vivo and in vitro, and osteopenia, indicating that PKD1 has a direct role to regulate osteoblast function and skeletal homeostasis. EXPERIMENTAL PROCEDURES

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“…A recent report showed that collagen type 2 is also expressed in the kidney [19]. Notably, the Ihh transcript has been detected in the proximal convoluted tubule and proximal straight tubule of the adult kidney [20].…”

Section: Discussionmentioning

confidence: 99%

Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor

Maeda

Schipani

Densmore

et al. 2010

Bone

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Indian hedgehog (Ihh) is essential for chondrocyte proliferation/differentiation and osteoblast differentiation during prenatal endochondral bone formation. Ihh expression in postnatal chondrocytes has a non-redundant role in maintaining a growth plate and sustaining trabecular bone after birth. Loss of Ihh in postnatal chondrocytes results in fusion of the growth plate and a decrease in trabecular bone. In order to normalize this abnormal chondrocyte phenotype and to investigate whether a putative rescue of the growth plate anomalies is sufficient to correct the severe alterations in the bone, we expressed a constitutively active PTH/PTHrP receptor, ( ; J mice, and this eventually led to the fusion of the growth plate at P14. In summary, we have demonstrated that expression of a Jansen receptor in chondrocytes was able to rescue abnormal chondrocyte differentiation but not impaired chondrocyte proliferation and the bone anomalies in mice lacking the Ihh gene in chondrocytes after birth. Taken together, our findings suggest that Ihh has both PTHrP -dependent and -independent functions during postnatal endochondral bone development.

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Col2-Cre recombinase is co-expressed with endogenous type II collagen in embryonic renal epithelium and drives development of polycystic kidney disease following inactivation of ciliary genes

Cited by 27 publications

References 29 publications

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

The ADPKD genespkd1a/bandpkd2regulate extracellular matrix formation

Conditional Disruption of Pkd1 in Osteoblasts Results in Osteopenia Due to Direct Impairment of Bone Formation

Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor

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