Abstract:A long-standing mystery in the centrosome field pertains to the origin of asymmetry within the organelle. The removal of daughter centriole-specific/enriched proteins (DCPs) and acquisition of distal appendages on the future mother centriole are two important steps in the generation of asymmetry. We find that DCPs are recruited sequentially, and their removal is abolished in cells lacking Talpid3 or C2CD3. We show that removal of certain DCPs constitutes another level of control for distal appendage (DA) assem… Show more
“…4b), which is a known distal appendage marker for the mother centriole, and the distal ends of centrioles are capped by CP110. A similar finding was also noted in a very recent report 23 . Based on our present findings, we conclude that when cells lose CEP120, they experience impairments in the recruitment of C2CD3 and Talpid3, but not CP110, to the distal ends of centrioles.Figure 4Super-resolution (3D-SIM) microscopic analysis of centriolar distal-end proteins.…”
Section: Resultssupporting
confidence: 91%
“…Talpid3 was previously reported to be essential for ciliary vesicle docking during ciliogenesis 20 . A very recent report showed that Talpid3 is physically associated with C2CD3 at the distal ends of centrioles and such an association is essential for centriole maturation and DA assembly 23 .…”
Centrosomal protein 120 (CEP120) was originally identified as a daughter centriole-enriched protein that participates in centriole elongation. Recent studies showed that
CEP120
gene mutations cause complex ciliopathy phenotypes in humans, including Joubert syndrome and Jeune asphyxiating thoracic dystrophy, suggesting that CEP120 plays an additional role in ciliogenesis. To investigate the potential roles of CEP120 in centriole elongation and cilia formation, we knocked out the
CEP120
gene in p53-deficient RPE1 cells using the CRISPR/Cas9 editing system, and performed various analyses. We herein report that loss of CEP120 produces short centrioles with no apparent distal and subdistal appendages. CEP120 knockout was also associated with defective centriole elongation, impaired recruitment of C2CD3 and Talpid3 to the distal ends of centrioles, and consequent defects in centriole appendage assembly and cilia formation. Interestingly, wild-type CEP120 interacts with C2CD3 and Talpid3, whereas a disease-associated CEP120 mutant (I975S) has a low affinity for C2CD3 binding and perturbs cilia assembly. Together, our findings reveal a novel role of CEP120 in ciliogenesis by showing that it interacts with C2CD3 and Talpid3 to assemble centriole appendages and by illuminating the molecular mechanism through which the CEP120 (I975S) mutation causes complex ciliopathies.
“…4b), which is a known distal appendage marker for the mother centriole, and the distal ends of centrioles are capped by CP110. A similar finding was also noted in a very recent report 23 . Based on our present findings, we conclude that when cells lose CEP120, they experience impairments in the recruitment of C2CD3 and Talpid3, but not CP110, to the distal ends of centrioles.Figure 4Super-resolution (3D-SIM) microscopic analysis of centriolar distal-end proteins.…”
Section: Resultssupporting
confidence: 91%
“…Talpid3 was previously reported to be essential for ciliary vesicle docking during ciliogenesis 20 . A very recent report showed that Talpid3 is physically associated with C2CD3 at the distal ends of centrioles and such an association is essential for centriole maturation and DA assembly 23 .…”
Centrosomal protein 120 (CEP120) was originally identified as a daughter centriole-enriched protein that participates in centriole elongation. Recent studies showed that
CEP120
gene mutations cause complex ciliopathy phenotypes in humans, including Joubert syndrome and Jeune asphyxiating thoracic dystrophy, suggesting that CEP120 plays an additional role in ciliogenesis. To investigate the potential roles of CEP120 in centriole elongation and cilia formation, we knocked out the
CEP120
gene in p53-deficient RPE1 cells using the CRISPR/Cas9 editing system, and performed various analyses. We herein report that loss of CEP120 produces short centrioles with no apparent distal and subdistal appendages. CEP120 knockout was also associated with defective centriole elongation, impaired recruitment of C2CD3 and Talpid3 to the distal ends of centrioles, and consequent defects in centriole appendage assembly and cilia formation. Interestingly, wild-type CEP120 interacts with C2CD3 and Talpid3, whereas a disease-associated CEP120 mutant (I975S) has a low affinity for C2CD3 binding and perturbs cilia assembly. Together, our findings reveal a novel role of CEP120 in ciliogenesis by showing that it interacts with C2CD3 and Talpid3 to assemble centriole appendages and by illuminating the molecular mechanism through which the CEP120 (I975S) mutation causes complex ciliopathies.
“…DAs comprise the proteins C2CD3 and Cep83 that are essential for the recruitment of additional DAs, such as Cep123/Cep89, SCLT1, LRRC45, Cep164, and FBF1 ( Fig. 1 A ; Tanos et al, 2013 ; Ye et al, 2014 ; Kurtulmus et al, 2018 ; Wang et al, 2018 ). DAs are essential at initial stages of cilia formation in order to establish the interaction between the basal body (a modified M-centriole) and the ciliary membrane compartment ( Schmidt et al, 2012 ; Tanos et al, 2013 ).…”
Distal appendages (DAs) of the mother centriole are essential for the initial steps of ciliogenesis in G1/G0 phase of the cell cycle. DAs are released from centrosomes in mitosis by an undefined mechanism. Here, we show that specific DAs lose their centrosomal localization at the G2/M transition in a manner that relies upon Nek2 kinase activity to ensure low DA levels at mitotic centrosomes. Overexpression of active Nek2A, but not kinase-dead Nek2A, prematurely displaced DAs from the interphase centrosomes of immortalized retina pigment epithelial (RPE1) cells. This dramatic impact was also observed in mammary epithelial cells with constitutively high levels of Nek2. Conversely, Nek2 knockout led to incomplete dissociation of DAs and cilia in mitosis. As a consequence, we observed the presence of a cilia remnant that promoted the asymmetric inheritance of ciliary signaling components and supported cilium reassembly after cell division. Together, our data establish Nek2 as an important kinase that regulates DAs before mitosis.
“…So far, 16 subtypes have been identified in OFDS, where all appear to represent a classic ciliopathy, with the disease genes coding for ciliary proteins . The OFD1 protein is mainly found within the basal body/centrosome, where it is important for centriole maturation and assembly of subdistal appendages . Mouse Ofd1 is required for formation of primary cilia and determination of left–right asymmetry .…”
In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor’s disease of oral‐facial‐digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next‐generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long‐term outcome was enabled for 5 recipients.
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