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Etude du complexe CEP90-FOPNL et OFD1 dans le processus d’ancrage des corps basaux

Abstract : Centrioles are highly conserved structures throughout evolution. They are organized in a 9-fold symmetry of microtubule triplets. In animals, centrioles are building blocks of the centrosome. The centrosome is the main organizing center of microtubules and is necessary for fundamental processes such as cell division and polarity. Under specific conditions, the mother centriole is able to migrate and anchor to a cell membrane to build a cilium. The anchoring process involves the distal extremity of the mother centriole and in particular the distal appendages. During ciliogenesis, the mother centriole matures and is called the basal body. The distal appendages mature in transition fibers and determine the proximal extremity of the transition zone, which acts as a filter to ensure the specificity of the protein and lipid composition of the cilium. During evolution, the structure of cilia is highly conserved, despite variations between organisms have been observed. Cilia play an essential role in signaling and / or motility. Consequently, in humans, rare genetic diseases originate from ciliary defects causing poly-malformation syndromes called ciliopathies. During my thesis, I was interested in identifying new actors of basal bodies anchoring using two complementary models: human cell cultures and Paramecium Tetraurelia. The basal bodies in Paramecium are all anchored to the plasma membrane and did not display any centriolar stages. Consequently, in this organism, anchoring defects are characterized by the presence of easily observable non-anchored basal bodies. Using this model, members of the team have already characterized the involvement of 4 proteins in the basal bodies anchoring: Cen2, OFD1, FOPNL and Cen3. In human, FOPNL, OFD1 and MNR form a complex involved in ciliogenesis, MNR and OFD1 both being involved in ciliopathies. To The search of novel actors involved in the basal body anchoring process has been achieved using BioID, a proximity identification technic, using FOPNL as a bait. We determined that the CEP90 protein is localized in the close environment of FOPNL. In human cells, CEP90 shares the same localization as FOPNL and OFD1 at centrioles and centriolar satellites and is also involved in ciliopathy. Using a super-resolution imaging technique called expansion microscopy, we show that CEP90, FOPNL, and OFD1 are organized in 9-fold symmetry at the distal part of the centrioles and basal bodies, close to the distal appendage protein CEP83. The recruitment of CEP90, FOPNL and OFD1 at basal bodies is interdependent and the absence of one of these proteins leads to basal body anchoring defects in Paramecium. In mammals, the depletion of FOPNL or CEP90 affects the recruitment of 3 distal appendage proteins (CEP83, CEP89 and CEP164). In mammalian cells, we demonstrated that CEP90 and OFD1 are recruited during duplication on early born procentrioles and that the co-overexpression of MNR and CEP90 is sufficient to recruit OFD1 and CEP83 along the microtubule network. Altogether these results shed new light on the basal body anchoring process. In addition, the early recruitment of CEP90, FOPNL and OFD1 complex on newly born procentrioles led us to propose that the localization of the complex specify the future location of the distal appendages. Finally, in this thesis, we show that CEP90, FOPNL and OFD1 is functionally conserved from Paramecium to mammalian cells despite it is absent in some phyla such as Drosophila and C.elegans.
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Submitted on : Tuesday, April 12, 2022 - 12:48:08 PM
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  • HAL Id : tel-03638718, version 1

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Pierrick Le Borgne. Etude du complexe CEP90-FOPNL et OFD1 dans le processus d’ancrage des corps basaux. Organisation et fonctions cellulaires [q-bio.SC]. Université Paris-Saclay, 2022. Français. ⟨NNT : 2022UPASL009⟩. ⟨tel-03638718⟩

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