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Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease [P15]

ABSTRACT: Mutations that disrupt centrosome biogenesis or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, how centrosome dysfunction results in the kidney disease phenotypes remains unknown. Here, we examined the consequences of conditional knockout of the ciliopathy gene Cep120, essential for centrosome duplication, in the nephron and collecting duct progenitor niches of the mouse embryonic kidney. Cep120 loss led to reduced abundance of both cap mesenchyme and ureteric bud populations, due to a combination of delayed mitosis, increased apoptosis, and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis, and decline in kidney function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for development, fibrosis, and cystogenesis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney morphogenesis, and identifies new therapeutic targets for patients with renal centrosomopathies.

ORGANISM(S): Mus musculus

PROVIDER: GSE249689 | GEO | 2023/12/08

REPOSITORIES: GEO

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Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease

Project description:Mutations that disrupt centrosome biogenesis or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, how centrosome dysfunction results in the kidney disease phenotypes remains unknown. Here, we examined the consequences of conditional knockout of the ciliopathy gene Cep120, essential for centrosome duplication, in the nephron and collecting duct progenitor niches of the mouse embryonic kidney. Cep120 loss led to reduced abundance of both cap mesenchyme and ureteric bud populations, due to a combination of delayed mitosis, increased apoptosis, and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis, and decline in kidney function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for development, fibrosis, and cystogenesis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney morphogenesis, and identifies new therapeutic targets for patients with renal centrosomopathies.

2023-12-08 | GSE249693 | GEO

Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease [Embryonic]

2023-12-08 | GSE249692 | GEO

Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease [P15]

Project description:Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease [P15]

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Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease

Project description:Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease

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Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease [Embryonic]

Project description:Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease [Embryonic]

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Centrosome amplification is sufficient to promote spontaneous tumorigenesis in mammals

Project description:Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of human cancer remains unclear. Here, we report the creation of a mouse model in which centrosome number can be persistently increased in the absence of additional genetic defects. We show that extra centrosomes increase tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive development of spontaneous tumors in multiple tissues. Tumors with centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship between centrosome amplification, genomic instability and tumor development. The sequences in this dataset result from random whole-genome DNA sequencing of spontaneous T- cell lymphomas, B-cell lymphomas, squamous cell carcinomas and one sarcoma from doxycycline-treated Plk4 mice.

2017-02-04 | E-MTAB-5043 | biostudies-arrayexpress

Molecular Signature of Centrosome Abnormalities in Multiple Myeloma

Project description:A large number of cancer-associated proteins involved in the cell cycle, DNA repair, chaperoning and nucleocytoplasmic transport etc. are involved in the control of centrosome number, duplication, centrosome formation and have been implicated as origin of centrosome abnormalities in cancer. In this study, we performed gene expression profiling with focusing on centrosome-related genes for determining the molecular signature characteristic for centrosome abnormalities in MM patients.

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OFD1 interacts with the Preinitiation complex of translation and regulates translation of specific targets in the kidney

Project description:OFD1 is a centrosomal/basal body protein codified by a transcript that when mutated results in OFD type I (OFDI) syndrome, a pleiotropic disorders associated with ciliary dysfunction. We demonstrate that components of the Preinitiation complex of translation (PIC) colocalize to the centrosome and interact with OFD1. We showed that OFD1 functionally controls the protein synthesis machinery, modulating the translation of specific mRNAs in the kidney. Our results indicate a new role for a centrosomal/basal body protein. The dataset contains the microarray data on total and polysomal RNA from control and Ofd1-IND mutant kidneys at P8.

2017-03-15 | E-MTAB-2827 | biostudies-arrayexpress

RNA-seq of cells with centrosome amplification

Project description:Centrosome amplification induces proliferation arrest and cell invasion. The fate of centrosome amplification cells are studied here.

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Centrosome amplification triggers tumorigenesis in p53 deficient epidermis

Project description:While aneuploidy is found in more than 90% of solid tumors, it is unclear whether aneuploidy is the cause or the consequence of tumorigenesis. Different mouse models deficient in centrosomal or spindle checkpoint proteins that induce aneuploidy show either a promotion or a decrease in tumorigenesis depending on the tissues and the types of oncogenic stimuli. To investigate the effects of aneuploidy in skin development and tumorigenesis, we used Plk4 over-expression (Plk4OE) during epidermal development to assess centrosome amplification and aneuploidy. We found that PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, consequently led to p53 stabilization and apoptosis of epidermal progenitors. This delayed epidermal stratification and induced lethal skin barrier defect in 50% of the mice. Plk4 transgene expression was shutdown postnatally in the surviving mice and PLK4OE mice never developed spontaneous skin tumors. Concomitant Plk4OE and P53 deletion (PLK4OE/p53cKO) rescued the defects in differentiation and stratification. Unexpectedly, p53 deletion did not rescue the apoptosis or eventual elimination of the cells overexpressing PLK4 and presenting multiple centrosomes. Remarkably, the short term presence of cells with supernumerary centrosomes postnatally was sufficient to generate aneuploidy and triggered spontaneous skin cancers with complete penetrance. These results reveal for the first time that aneuploidy induced by centrosome amplification, even if transient, can trigger tumorigenesis.

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