scholarly journals The Talpid3 gene (KIAA0586) encodes a centrosomal protein that is essential for primary cilia formation

Development ◽  
2009 ◽  
Vol 136 (4) ◽  
pp. 655-664 ◽  
Author(s):  
Y. Yin ◽  
F. Bangs ◽  
I. R. Paton ◽  
A. Prescott ◽  
J. James ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Centrosomal Protein ◽  
Cilia Formation

scholarly journals C3G (RapGEF1) localizes to the mother centriole and regulates centriole division and primary cilia dynamics

2019 ◽  
Author(s):  
Sanjeev Chavan Nayak ◽  
Vegesna Radha
Keyword(s):  
Embryonic Development ◽  
Primary Cilia ◽  
Negative Regulator ◽  
Ciliated Cells ◽  
Wild Type ◽  
Centrosomal Protein ◽  
Over Expression ◽  
Cilia Formation ◽  
Mother Centriole ◽  
Summary Statement

AbstractC3G (RapGEF1), a negative regulator of β-catenin, plays a role in cell differentiation and is essential for early embryonic development in mice. In this study, we identify C3G as a centrosomal protein that regulates centriole division and primary cilia dynamics. C3G is present at the centrosome in interphase as well as mitotic cells, but is absent at the centrioles in differentiated myotubes. It interacts with, and co-localizes with cenexin in the mother centriole. Stable clone of cells depleted of C3G by CRISPR/Cas9 showed reduction in cenexin protein, and presence of supernumerary centrioles. Over-expression of C3G resulted in inhibition of centrosome division in normal and hydroxyurea treated cells. Proportion of ciliated cells is higher, and cilia length longer in C3G knockout cells. C3G inhibits cilia formation and length dependent on its catalytic activity. Unlike wild type cells, C3G depleted cells inefficiently retracted their cilia upon stimulation to reenter the cell cycle, and proliferated slowly, arresting in G1. We conclude that C3G inhibits centriole division and maintains ciliary homeostasis, properties that may be important for its role in embryonic development.Summary statementWe identify C3G as a centrosomal protein and regulator of centriole number, primary cilia length and resorption. These properties are important for its role in embryogenesis, and suggest that mutations in C3G could cause ciliopathies.

scholarly journals CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels

2020 ◽  
Author(s):  
André Brás Gonçalves ◽  
Beinta Biskopstø Joensen ◽  
Sarah Kirstine Hasselbalch ◽  
Pernille Martens ◽  
Signe Krogh Ohlsen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Ubiquitin Ligase ◽  
Primary Cilia ◽  
E3 Ubiquitin Ligase ◽  
Centrosomal Protein ◽  
Ubiquitin Ligase Complex ◽  
Cilia Formation ◽  
Retinal Cone ◽  
Dependent Mechanism

AbstractCEP78 is a centrosomal protein implicated in ciliogenesis and ciliary length control, and mutations in the CEP78 gene cause retinal cone-rod dystrophy associated with hearing loss. However, the mechanism by which CEP78 affects cilia formation is unknown. Based on a recently-discovered disease-causing CEP78 p.L150S mutation, we identified the disease-relevant interactome of CEP78. We confirmed that CEP78 interacts with the EDD1-DYRK2-DDB1VPRBP E3 ubiquitin ligase complex, which is involved in CP110 ubiquitination and degradation, and identified a novel interaction between CEP78 and CEP350 that is weakened by the CEP78L150S mutation. We show that CEP350 promotes centrosomal recruitment and stability of CEP78, which in turn leads to centrosomal recruitment of EDD1. Consistently, cells lacking CEP78 display significantly increased cellular and centrosomal levels of CP110, and depletion of CP110 in CEP78-deficient cells restored ciliation frequency to normal. We propose that CEP78 functions downstream of CEP350 to promote ciliogenesis by negatively regulating CP110 levels via an EDD1-dependent mechanism.

scholarly journals CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
André B Goncalves ◽  
Sarah K Hasselbalch ◽  
Beinta B Joensen ◽  
Sebastian Patzke ◽  
Pernille Martens ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Ubiquitin Ligase ◽  
Primary Cilia ◽  
E3 Ubiquitin Ligase ◽  
Centrosomal Protein ◽  
Ubiquitin Ligase Complex ◽  
Cilia Formation ◽  
Retinal Cone ◽  
Dependent Mechanism

CEP78 is a centrosomal protein implicated in ciliogenesis and ciliary length control, and mutations in the CEP78 gene cause retinal cone-rod dystrophy associated with hearing loss. However, the mechanism by which CEP78 affects cilia formation is unknown. Based on a recently discovered disease-causing CEP78 p.L150S mutation, we identified the disease-relevant interactome of CEP78. We confirmed that CEP78 interacts with the EDD1-DYRK2-DDB1VPRBP E3 ubiquitin ligase complex, which is involved in CP110 ubiquitination and degradation, and identified a novel interaction between CEP78 and CEP350 that is weakened by the CEP78L150S mutation. We show that CEP350 promotes centrosomal recruitment and stability of CEP78, which in turn leads to centrosomal recruitment of EDD1. Consistently, cells lacking CEP78 display significantly increased cellular and centrosomal levels of CP110, and depletion of CP110 in CEP78-deficient cells restored ciliation frequency to normal. We propose that CEP78 functions downstream of CEP350 to promote ciliogenesis by negatively regulating CP110 levels via an EDD1-dependent mechanism.

scholarly journals Protein Kinase A-Mediated Septin7 Phosphorylation Disrupts Septin Filaments and Ciliogenesis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 361
Author(s):  
Han-Yu Wang ◽  
Chun-Hsiang Lin ◽  
Yi-Ru Shen ◽  
Ting-Yu Chen ◽  
Chia-Yih Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Primary Cilia ◽  
Cell Growth And Migration ◽  
Filament Dynamics ◽  
Gtp Binding ◽  
Cilia Formation ◽  
And Migration ◽  
Septin Filament ◽  
Kinase A

Septins are GTP-binding proteins that form heteromeric filaments for proper cell growth and migration. Among the septins, septin7 (SEPT7) is an important component of all septin filaments. Here we show that protein kinase A (PKA) phosphorylates SEPT7 at Thr197, thus disrupting septin filament dynamics and ciliogenesis. The Thr197 residue of SEPT7, a PKA phosphorylating site, was conserved among different species. Treatment with cAMP or overexpression of PKA catalytic subunit (PKACA2) induced SEPT7 phosphorylation, followed by disruption of septin filament formation. Constitutive phosphorylation of SEPT7 at Thr197 reduced SEPT7‒SEPT7 interaction, but did not affect SEPT7‒SEPT6‒SEPT2 or SEPT4 interaction. Moreover, we noted that SEPT7 interacted with PKACA2 via its GTP-binding domain. Furthermore, PKA-mediated SEPT7 phosphorylation disrupted primary cilia formation. Thus, our data uncover the novel biological function of SEPT7 phosphorylation in septin filament polymerization and primary cilia formation.

scholarly journals FBW7 couples structural integrity with functional output of primary cilia

2020 ◽  
Author(s):  
Eleni Petsouki ◽  
Vasileios Gerakopoulos ◽  
Nicholas Szeto ◽  
Wenhan Chang ◽  
Mary Beth Humphrey ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Structural Integrity ◽  
Stem Cell Differentiation ◽  
Bone Architecture ◽  
Structural Defects ◽  
Independent Manner ◽  
Mesenchymal Stem Cell Differentiation ◽  
Cilia Formation ◽  
Length Changes ◽  
Msc Differentiation

AbstractStructural defects in cilia have robust effects in diverse tissues and systems. However, how ciliary length changes influence signaling output are unknown. Here, we examined the functional role of a ciliary length control mechanism whereby FBW7-mediated destruction of NDE1 positively regulated ciliary length, in mesenchymal stem cell differentiation. We show that FBW7 functions as a master regulator of both negative (NDE1) and positive (TALPID3) regulators of ciliogenesis, with an overall positive net effect on cilia formation, MSC differentiation, and bone architecture. Deletion of Fbxw7 suppresses ciliation, Hedgehog activity, and differentiation, which are rescued in Fbxw7/Nde1-null cells. However, despite formation of abnormally long cilia in Nde1-null cells, MSC differentiation is suppressed. NDE1 promotes MSC differentiation by increasing the activity of the Hedgehog pathway by direct binding and enhancing GLI2 activity in a cilia-independent manner. We propose that ciliary structure-function coupling is determined by intricate interactions of structural and functional proteins.

scholarly journals Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chan Hee Lee ◽  
Do Kyeong Song ◽  
Chae Beom Park ◽  
Jeewon Choi ◽  
Gil Myoung Kang ◽  
...  
Keyword(s):  
Early Life ◽  
Primary Cilia ◽  
Maternal Nutrition ◽  
Hypothalamic Neurons ◽  
Axonal Projections ◽  
Early Life Programming ◽  
Body Weights ◽  
Cilia Formation ◽  
Obesity In Mice ◽  
Underlying Mechanisms

AbstractHypothalamic neurons including proopiomelanocortin (POMC)-producing neurons regulate body weights. The non-motile primary cilium is a critical sensory organelle on the cell surface. An association between ciliary defects and obesity has been suggested, but the underlying mechanisms are not fully understood. Here we show that inhibition of ciliogenesis in POMC-expressing developing hypothalamic neurons, by depleting ciliogenic genes IFT88 and KIF3A, leads to adulthood obesity in mice. In contrast, adult-onset ciliary dysgenesis in POMC neurons causes no significant change in adiposity. In developing POMC neurons, abnormal cilia formation disrupts axonal projections through impaired lysosomal protein degradation. Notably, maternal nutrition and postnatal leptin surge have a profound impact on ciliogenesis in the hypothalamus of neonatal mice; through these effects they critically modulate the organization of hypothalamic feeding circuits. Our findings reveal a mechanism of early life programming of adult adiposity, which is mediated by primary cilia in developing hypothalamic neurons.

scholarly journals Induction of Ran GTP drives ciliogenesis

2011 ◽  
Vol 22 (23) ◽  
pp. 4539-4548 ◽  
Author(s):  
Shuling Fan ◽  
Eileen L. Whiteman ◽  
Toby W. Hurd ◽  
Jeremy C. McIntyre ◽  
John F. Dishinger ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Protein Transport ◽  
Nucleocytoplasmic Transport ◽  
Small Gtpase ◽  
Basal Bodies ◽  
Ciliary Protein ◽  
Cilia Formation ◽  
Ran Gtp ◽  
New Evidence ◽  
Gtpase Ran

The small GTPase Ran and the importin proteins regulate nucleocytoplasmic transport. New evidence suggests that Ran GTP and the importins are also involved in conveying proteins into cilia. In this study, we find that Ran GTP accumulation at the basal bodies is coordinated with the initiation of ciliogenesis. The Ran-binding protein 1 (RanBP1), which indirectly accelerates Ran GTP → Ran GDP hydrolysis and promotes the dissociation of the Ran/importin complex, also localizes to basal bodies and cilia. To confirm the crucial link between Ran GTP and ciliogenesis, we manipulated the levels of RanBP1 and determined the effects on Ran GTP and primary cilia formation. We discovered that RanBP1 knockdown results in an increased concentration of Ran GTP at basal bodies, leading to ciliogenesis. In contrast, overexpression of RanBP1 antagonizes primary cilia formation. Furthermore, we demonstrate that RanBP1 knockdown disrupts the proper localization of KIF17, a kinesin-2 motor, at the distal tips of primary cilia in Madin–Darby canine kidney cells. Our studies illuminate a new function for Ran GTP in stimulating cilia formation and reinforce the notion that Ran GTP and the importins play key roles in ciliogenesis and ciliary protein transport.

scholarly journals CEP19 cooperates with FOP and CEP350 to drive early steps in the ciliogenesis programme

Open Biology ◽  
2017 ◽  
Vol 7 (6) ◽  
pp. 170114 ◽  
Author(s):  
Bahareh A. Mojarad ◽  
Gagan D. Gupta ◽  
Monica Hasegan ◽  
Oumou Goudiam ◽  
Renata Basto ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Three Dimensional ◽  
Structured Illumination ◽  
Loss Of Function ◽  
Structured Illumination Microscopy ◽  
C Terminus ◽  
Interaction Partners ◽  
Cilia Formation ◽  
Mother Centriole ◽  
Section Electron

Primary cilia are microtubule-based sensory organelles necessary for efficient transduction of extracellular cues. To initiate cilia formation, ciliary vesicles (CVs) are transported to the vicinity of the centrosome where they dock to the distal end of the mother centriole and fuse to initiate cilium assembly. However, to this date, the early steps in cilia formation remain incompletely understood. Here, we demonstrate functional interplay between CEP19, FOP and CEP350 in ciliogenesis. Using three-dimensional structured-illumination microscopy (3D-SIM) imaging, we mapped the relative spatial distribution of these proteins at the distal end of the mother centriole and show that CEP350/FOP act upstream of CEP19 in their recruitment hierarchy. We demonstrate that CEP19 CRISPR KO cells are severely impaired in their ability to form cilia, analogous to the loss of function of CEP19 binding partners FOP and CEP350. Notably, in the absence of CEP19 microtubule anchoring at centromes is similar in manner to its interaction partners FOP and CEP350. Using GFP-tagged deletion constructs of CEP19, we show that the C-terminus of CEP19 is required for both its localization to centrioles and for its function in ciliogenesis. Critically, this region also mediates the interaction between CEP19 and FOP/CEP350. Interestingly, a morbid-obesity-associated R82* truncated mutant of CEP19 cannot ciliate nor interact with FOP and CEP350, indicative of a putative role for CEP19 in ciliopathies. Finally, analysis of CEP19 KO cells using thin-section electron microscopy revealed marked defects in the docking of CVs to the distal end of the mother centrioles. Together, these data demonstrate a role for the CEP19, FOP and CEP350 module in ciliogenesis and the possible effect of disrupting their functions in ciliopathies.

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