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Mireille Montcouquiol, Jérôme Ezan

A molecular link between planar cell polarity and cilium migration

Le 10 septembre 2013

Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton
Jerome Ezan, Léa Lasvaux, Aysegul Gezer, Ana Novakovic, Helen May-Simera, Edwige Belotti, Anne-Catherine Lhoumeau, Lutz Birnbaumer, Sandra Beer-Hammer,Jean-Paul Borg, André Le Bivic, Bernd Nürnberg, Nathalie Sans & Mireille Montcouquiol
Nature Cell Biology 15, 1107–1115 (2013) doi:10.1038/ncb2819
PubMed

Mireille Montcouquiol: How was this study developed ? 


Our lab has a strong interest in cell and tissue polarization. Uniquely in the neuroscience field, our lab is using two models - the inner ear and the brain - in order to understand the role(s) of Planar Cell Polarity (PCP) during development and in adulthood. This work is the result of a strong convergence of interest between Jérôme Ezan who joined the lab in 2010 after completing a post-doc in the US and myself  who has been working on PCP in mammals for the last 10 years. This work is also the result of a nice collaboration with the group of Bernd Nürnberg (Tübingen, Germany), a specialist of Gαi-proteins and two other groups in Marseille, specialized in polarity complexes: André LeBivic (IBDML) and Jean-Paul Borg (CRCM).

What are the major results of this study?
This project originates from a very simple concept: we hypothesized that the molecular polarity complexes that control centrosome position during asymmetric cell division are used in postmitotic cells to control cilium position. As a result, we identify the elusive molecular and cellular links between PCP signaling and cilium. To demonstrate this, we use the inner ear, and most specifically the cochlear epithelium, that has been widely accepted as one of the best model to analyze and quantify core PCP in mammals.
More specifically, we demonstrate that an original molecular mechanism controls cilium positioning and regulates PCP in epithelial cells:
1) We identify a PCP pathway molecularly different from the classical "core" PCP pathway that responds to early cues from the core PCP pathway
2) We show that this pathway is comprised of two opposite proteins complexes: The G-protein alpha i (Gαi)/mammalian Partner of Inscuteable (mPins) complex on one side, and the classical partitioning defective (PAR-6b).atypical PKC (aPKC) complex on the other side. (see below  Figure 1).
3) Finally, we link Gαi function to a cytoskeleton-dependent control of cilia migration (see below Figure 2).

One of the really interesting outcomes of our study is that the position of the cilium in a postmitotic cell needs to be controlled by polarity cues, something obvious in ependymal or node cells, but that we believe is true for other cell type, including neurons or glial cells. It is often overlooked that pretty much every cell in our organism is ciliated and polarized in its own way, and that disruption of the intrinsic or tissue polarity will affect the function of the cell and/or the tissue.

Why is it important to understand the link between PCP and cilium?
The molecular relationship between PCP and cilium has been the center of a lot of interest and controversy in recent years. PCP was originally identified in invertebrate's epithelia, which is why most studies pertain to this tissue. Ten years ago, our pioneering work led to the identification of two of the first of these PCP genes in mammals, Vangl2 and Scrib1, (Montcouquiol et al., 2003), and Celrs1 (Curtin et al., 2003). Since then, an explosion of studies revealed the importance of PCP signaling in many tissues including muscles, heart, vessels, bones, or the nervous system, and related pathologies (neural tube defects, polycystic kidney disease, cardiac, muscles, vessels or bones malformation), and more recently mutations on PCP proteins have been identified in autistic and epileptic patients. Although scarce, data on PCP signaling disruption in adult mice, including ours, have revealed sociability defects and memory imbalance, typical of ASD (Moreau et al., 2010). On the other hand, the ciliary function appears to be critical not only during development of the central nervous system (Louvi et al., 2011), but also during adult neurogenesis (Han et al. 2008) and synaptic integration in adults neurons (Kumamoto et al., 2012).

In the last 5 years, various studies have showed that mutations affecting ciliary components and those affecting core PCP genes can lead to similar but not completely congruent phenotypes, suggesting the existence of another PCP signaling that would control the apical migration of the cilium in a cell autonomous fashion. Also, recent studies have emphasized some similarities between PCP-related pathologies and ciliopathies. We partially elucidate this link in this paper.

Below Fig 1 and Fig2, click to enlarge...

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Jérôme Ezan (jerome.ezan @ inserm.fr)
Dernière mise à jour le 11.09.2013

Jérôme Ezan


These en 2005: Etude des proprietés angiogeniques d'un inhibiteur de la voie Wnt. (Dr Duplaa, Inserm Pessac)
Post-doc (2006-2010): Polarité, neurogenese et determination des axes chez le xenope (Pr Sokol, Mount Sinai School of Medecine, New York, USA)
Jérôme Ezan PubMed