Biology subjects

Mahuzier, A.

Publications and source records attributed to Mahuzier, A..

3 recordsLinked to original sources

bioRxiv2024

The ANKS3/BICC1 protein complex is a master post-transcriptional regulator of NPHP1 ciliopathy gene transcripts

Ciliopathies are a class of multi-systemic genetic diseases characterized by ciliary dysfunction. Here, we report a novel ANKS3 variant in patients with a renal ciliopathy known as nephronophthisis (NPH) associated with hepatic defects. ANKS3 is an ankyrin and sterile alpha motif domain-containing protein that interacts with many NPH proteins as well as with BICC1, an RNA-binding protein involved in renal cystic diseases. The pathogenic effect of the ANKS3 mutation was validated in the zebrafish mutant and knock-in rat model, the latter showing urine concentration defect and tubular dilatations similar to NPH patients. In addition, cilia morphology and function as well as epithelialization of kidney tubular cells was affected by loss or mutation of ANKS3. Finally, our results evidenced that these classically renal ciliopathy-associated phenotypes were linked to the negative regulation of BICC1 by ANKS3 which binds to transcripts of the major NPH gene NPHP1 and mediates their decay through the AGO2-RISC complex and recruitment into P-bodies. Altogether, our findings suggest that the ANKS3/BICC1 complex is a key post-transcriptional regulator of NPHP1 transcript stability, providing another level of regulation of cilium biogenesis and kidney homeostasis, as well as an unusual mechanism leading to NPH-related ciliopathies.

pathology↗

bioRxiv2023

Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation.

Ependymal cells (ECs) are multi-ciliated cells in the brain that contribute to cerebrospinal fluid flow. ECs are specified at embryonic stages but differentiate later in development. Differentiation depends on genes such as GEMC1 and MCIDAS with E2F4/5, but also on cell cycle related factors. In the mouse brain, we observe that nuclear deformation accompanies EC differentiation. Tampering with these deformations either by decreasing F-actin levels or by severing the link between the nucleus and the actin cytoskeleton blocks differentiation. Conversely, increasing F-actin by knocking out the Arp2/3 complex inhibitor Arpin or artificially deforming the nucleus activates differentiation. These data are consistent with actin polymerization triggering nuclear deformation and jump-starting the signaling that produces ECs. A player in this process is the retinoblastoma1 (RB1) protein whose phosphorylation prompts MCIDAS activation. Overall, this study reveals an important role for actin-based mechanical inputs to the nucleus as controlling factors in cell differentiation.

developmental biology↗

bioRxiv2018

Dynamics of centriole amplification in centrosome-depleted brain multiciliated progenitors

Centrioles are essential microtubule-based organelles organizing cilia and centrosomes. Their mode of biogenesis is semi-conservative: each pre-existing centriole scaffolds the formation of a new one, a process coordinated with the cell cycle. By contrast, multiciliated progenitors with two centrosomal centrioles massively amplify centrioles to support the nucleation of hundred of motile cilia and transport vital fluids. This occurs through cell type-specific organelles called deuterosomes, composed of centrosome-related elements, and is regulated by the cell cycle machinery. Deuterosome-dependent centriole amplification was proposed for decades to occur de novo, i.e. independently from pre-existing centrioles. Challenging this hypothesis, we recently reported an accumulation of procentriole and deuterosome precursors at the centrosomal daughter centriole during centriole amplification in brain multiciliated cells. Here we further investigate the relationship between the centrosome and the dynamic of centriole amplification by (i) characterizing the centrosome behavior during the centriole amplification dynamics and (ii) assessing the dynamics of amplification in centrosome-depleted cells. Surprisingly, although our data strengthen the centrosomal origin of amplified centrioles, we show limited consequences in deuterosome/centriole number when we deplete centrosomal centrioles. Interestingly, in absence of centrosomal centrioles, procentrioles are still amplified sequentially from a single focal region, characterized by microtubule convergence and pericentriolar material (PCM) self-assembly. The relevance of deuterosome association with the daughter centriole as well as the role of the PCM in the focal and sequential genesis of centrioles in absence of centrosomal centrioles are discussed.

cell biology↗