The Role of Centrosome Distal Appendage Proteins (DAPs) in Nephronophthisis and Ciliogenesis

Mansour, Fatma; Boivin, Félix; Shaheed, Iman B.; Schueler, Markus; Schmidt‐Ott, Kai M.

doi:10.3390/ijms222212253

Cited by 9 publications

(4 citation statements)

References 131 publications

(231 reference statements)

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“…In dividing cells, the two centrioles are duplicated once during S-phase to facilitate the formation of a bi-polar mitotic spindle and thus aid the correct segregation of chromosomes. In differentiating cells, they are essential for ciliogenesis and defects in centriole biogenesis are linked to severe developmental abnormalities, including microcephaly and kidney malfunction (Mansour et al , 2021; Phan & Holland, 2021). Centrosome aberrations frequently occur in cancer and are known to promote chromosomal instability (CIN), provoking aneuploidy (Chunduri & Storchová, 2019; Ganem et al , 2009; Levine & Holland, 2018).…”

Section: Introductionmentioning

confidence: 99%

Exact centriole counts are critical for B cell development but not function

Schapfl,

LoMastro,

Braun

et al. 2024

Preprint

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Centrioles define centrosome structure and function. Deregulation of centriole numbers can cause developmental defects and foster malignant disease. The p53 tumor suppressor limits the growth of cells lacking or harboring additional centrioles and can be engaged by the 'mitotic surveillance' or the 'PIDDosome pathway', respectively. Here, we show that early B cell progenitors frequently present extra centrioles that are rapidly lost during maturation. Increasing centriole counts beyond physiological levels by Polo-like kinase 4 (PLK4) overexpression induces apoptosis, suggesting clearance of such cells during development. Remarkably, this apoptotic response is independent of PIDD1 or p53, but can be blocked by excess BCL2. In contrast, loss of centrosomes upon Plk4 deletion arrests B cell development at the pro B cell stage. This defect can be rescued by co-deletion of Usp28, a critical component of the mitotic surveillance pathway that restores cell number and function in the absence of centrioles. In both scenarios, too many and too few centrosomes, mitochondrial apoptosis is engaged to kill B cells with abnormal centriole counts during their development with progenitor B cells being intolerant to centriole loss but permissive to centriole amplification. Unexpectedly, our findings show that centrioles are dispensable for mounting an effective humoral immune response.

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Section: Introductionmentioning

confidence: 99%

Exact centriole counts are critical for B cell development but not function

Schapfl,

LoMastro,

Braun

et al. 2024

Preprint

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“…A significant number of genes that are mutated in patients with cystic and fibrotic renal pathologies encode cilia-and centrosome-associated proteins [5][6][7] . The centrosome is the major microtubule-organizing center in mammalian cells, with important roles in regulating the microtubule cytoskeleton in interphase and mitosis 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

Cheng

Agwu

Shim

et al. 2023

Preprint

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Mutations that disrupt centrosome structure or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, it remains unclear how mutations in proteins essential for centrosome biogenesis impact embryonic kidney development. Here, we examined the consequences of conditional deletion of a ciliopathy gene, Cep120, in the two nephron progenitor niches of the embryonic kidney. Cep120 loss led to reduced abundance of both metanephric mesenchyme and ureteric bud progenitor populations. This was 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 filtration function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for branching morphogenesis, cystogenesis and fibrosis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney development, and identifies new therapeutic targets for renal centrosomopathies.

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“…The centrosomal protein 83 (CEP83) is a component of distal appendages (DAPs) of centrioles. DAPs are involved in the anchoring of the mother centriole to the cell membrane, an early and critical step in ciliogenesis ( Lo et al, 2019 ; Tanos et al, 2013 ; Yang et al, 2018 ; Kurtulmus et al, 2018 ; Wheway et al, 2015 ; Bowler et al, 2019 ; Failler et al, 2014 ; Shao et al, 2020 ; Mansour et al, 2021 ). CEP83 recruits other DAP components to the ciliary base, and loss of CEP83 disrupts ciliogenesis ( Tanos et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

The centrosomal protein 83 (CEP83) regulates human pluripotent stem cell differentiation toward the kidney lineage

Mansour

Hinze

Telugu

et al. 2022

eLife

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During embryonic development, the mesoderm undergoes patterning into diverse lineages including axial, paraxial, and lateral plate mesoderm (LPM). Within the LPM, the so-called intermediate mesoderm (IM) forms kidney and urogenital tract progenitor cells, while the remaining LPM forms cardiovascular, hematopoietic, mesothelial, and additional progenitor cells. The signals that regulate these early lineage decisions are incompletely understood. Here, we found that the centrosomal protein 83 (CEP83), a centriolar component necessary for primary cilia formation and mutated in pediatric kidney disease, influences the differentiation of human induced pluripotent stem cells (hiPSCs) towards intermediate mesoderm. We induced inactivating deletions of CEP83 in hiPSCs and applied a 7 day in vitro protocol of intermediate mesoderm kidney progenitor differentiation, based on timed application of WNT and FGF agonists. We characterized induced mesodermal cell populations using single cell and bulk transcriptomics and tested their ability to form kidney structures in subsequent organoid culture. While hiPSCs with homozygous CEP83 inactivation were normal regarding morphology and transcriptome, their induced differentiation into IM progenitor cells was perturbed. Mesodermal cells induced after 7 days of monolayer culture of CEP83-deficient hiPCS exhibited absent or elongated primary cilia, displayed decreased expression of critical IM genes (PAX8, EYA1, HOXB7), and an aberrant induction of LPM markers (e. g. FOXF1, FOXF2, FENDRR, HAND1, HAND2). Upon subsequent organoid culture, wildtype cells differentiated to form kidney tubules and glomerular-like structures, whereas CEP83-deficient cells failed to generate kidney cell types, instead upregulating cardiomyocyte, vascular, and more general LPM progenitor markers. Our data suggest that CEP83 regulates the balance of intermediate mesoderm and lateral plate mesoderm formation from human pluripotent stem cells, identifying a potential link between centriolar or ciliary function and mesodermal lineage induction.

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The Role of Centrosome Distal Appendage Proteins (DAPs) in Nephronophthisis and Ciliogenesis

Cited by 9 publications

References 131 publications

Exact centriole counts are critical for B cell development but not function

Exact centriole counts are critical for B cell development but not function

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

The centrosomal protein 83 (CEP83) regulates human pluripotent stem cell differentiation toward the kidney lineage

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