Neurocentre Magendie

Mireille MONTCOUQUIOL




Chercheur

Tél : 33(0)5 57 57 37 62 / 33(0)5 57 57 37 59
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Cursus:
PhD Université Montpellier II (1997)
Postdoctoral Research Associate, UVA, Charlottesville, USA (1997-2002)
NIH Postdoctoral fellow, MD, USA (2002-2005)
CR1 INSERM (2007)
DR2 INSERM (2014)

Expertise: cell biology, development, neuroscience, imaging



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46 publication(s) depuis Novembre 1997:


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* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en


21/06/2018 | cell physiol biochem
Galphai Proteins are Indispensable for Hearing.
Beer-Hammer S, Lee SC, Mauriac SA, Leiss V, Groh IAM, Novakovic A, Piekorz RP, Bucher K, Chen C, Ni K, Singer W, Harasztosi C, Schimmang T, Zimmermann U, Pfeffer K, Birnbaumer L, Forge A, Montcouquiol M, Knipper M, Nurnberg B, Ruttiger L

Abstract:
BACKGROUND/AIMS: From invertebrates to mammals, Galphai proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Galphai3-deficiency in pre-hearing murine cochleae pointed to a role of Galphai3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary ('hair') bundle, a requirement for the progression of mature hearing. We found that the lack of Galphai3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear. METHODS: Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Galphai proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with functional tests were applied to dissect essential and redundant functions of different Galphai isoforms and to assign specific defects to outer or inner hair cells, the auditory nerve, satellite cells or central auditory neurons. RESULTS: Here we report that lack of Galphai3 but not of the ubiquitously expressed Galphai2 elevates hearing threshold, accompanied by impaired hair bundle elongation and shape in high-frequency cochlear regions. During the crucial reprogramming of the immature inner hair cell (IHC) synapse into a functional sensory synapse of the mature IHC deficiency for Galphai2 or Galphai3 had no impact. In contrast, double-deficiency for Galphai2 and Galphai3 isoforms results in abnormalities along the entire tonotopic axis including profound deafness associated with stereocilia defects. In these mice, postnatal IHC synapse maturation is also impaired. In addition, the analysis of conditional versus global Galphai3-deficient mice revealed that the amplitude of ABR wave IV was disproportionally elevated in comparison to ABR wave I indicating that Galphai3 is selectively involved in generation of neural gain during auditory processing. CONCLUSION: We propose a so far unrecognized complexity of isoform-specific and overlapping Galphai protein functions particular during final differentiation processes.




25/05/2018 | Nat Commun   IF 12.4
Author Correction: Defective Gpsm2/Galphai3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.
Mauriac SA, Hien YE, Bird JE, Carvalho SD, Peyroutou R, Lee SC, Moreau MM, Blanc JM, Gezer A, Medina C, Thoumine O, Beer-Hammer S, Friedman TB, Ruttiger L, Forge A, Nurnberg B, Sans N, Montcouquiol M

Abstract:
This corrects the article DOI: 10.1038/ncomms14907.




03/06/2017 | Neuroscience   IF 3.4
The embryonic development of hindbrain respiratory networks is unaffected by mutation of the planar polarity protein Scribble.
Chevalier M, Cardoit L, Moreau M, Sans N, Montcouquiol M, Simmers J, Thoby-Brisson M

Abstract:
The central command for breathing arises mainly from two interconnected rhythmogenic hindbrain networks, the parafacial respiratory group (pFRG or epF at embryonic stages) and the preBotzinger complex (preBotC), which are comprised of a limited number of neurons located in confined regions of the ventral medulla. In rodents, both networks become active toward the end of gestation but little is known about the signaling pathways involved in their anatomical and functional establishment during embryogenesis. During embryonic development, epF and preBotC neurons migrate from their territories of origin to their final positions in ventral brainstem areas. Planar Cell Polarity (PCP) signaling, including the molecule Scrib, is known to control the developmental migration of several hindbrain neuronal groups. Accordingly, a homozygous mutation of Scrib leads to severe disruption of hindbrain anatomy and function. Here, we aimed to determine whether Scrib is also involved in the prenatal development of the hindbrain nuclei controlling breathing. We combined immunostaining, calcium imaging and electrophysiological recordings of neuronal activity in isolated in vitro preparations. In the Scrib mutant, despite severe neural tube defects, epF and preBotC neurons settled at their expected hindbrain positions. Furthermore, both networks remained capable of generating rhythmically organized, respiratory-related activities and exhibited normal sensitivity to pharmacological agents known to modify respiratory circuit function. Thus Scrib is not required for the proper migration of epF and preBotC neurons during mouse embryogenesis. Our findings thus further illustrate the robustness and specificity of the developmental processes involved in the establishment of hindbrain respiratory circuits.




07/04/2017 | Nat Commun   IF 12.4
Defective Gpsm2/Galphai3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.
Mauriac SA, Hien YE, Bird JE, Carvalho SD, Peyroutou R, Lee SC, Moreau MM, Blanc JM, Geyser A, Medina C, Thoumine O, Beer-Hammer S, Friedman TB, Ruttiger L, Forge A, Nurnberg B*, Sans N*, Montcouquiol M*

Abstract:
Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Galphai3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an approximately 200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Galphai3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Galphai3 in the regulation of actin dynamics in epithelial and neuronal tissues.




27/03/2017 | Development   IF 5.4
Wnts contribute to neuromuscular junction formation through distinct signaling pathways.
Messeant J, Ezan J, Delers P, Glebov K, Marchiol C, Lager F, Renault G, Tissir F, Montcouquiol M, Sans N, Legay C, Strochlic L

Abstract:
Understanding the developmental steps shaping the formation of the neuromuscular junction (NMJ) connecting motoneurons to skeletal muscle fibers, is critical. Wnt morphogens are key players in the formation of this specialized peripheral synapse. Yet, the individual and collaborative functions of Wnts as well as their downstream pathways remain poorly understood at the NMJ. Here, we demonstrate through Wnt4 and Wnt11 gain of function studies in culture or in mice that Wnts enhance acetylcholine receptor (AChR) clustering and motor axon outgrowth. In contrast, loss of Wnt11 or Wnt-dependent signaling in vivo decreases AChR clustering and motor nerve terminal branching. Both Wnt4 and Wnt11 stimulate AChR clustering and mRNA downstream activation of the beta-catenin pathway. Strikingly, Wnt4 and Wnt11 co-immunoprecipitate with Vangl2, a core component of the Planar Cell Polarity (PCP) pathway, which accumulates at embryonic NMJ. Moreover, mice bearing a Vangl2 loss of function mutation (looptail) exhibit a decreased number of AChR clusters and overgrowth of motor axons bypassing AChR clusters. Taken together, our results provide genetic and biochemical evidences that Wnt4 and Wnt11 cooperatively contribute to mammalian NMJ formation through activation of both the canonical and Vangl2-dependent core PCP pathways.




22/11/2016 | Cereb Cortex   IF 6.3
Activity-Dependent Neuroplasticity Induced by an Enriched Environment Reverses Cognitive Deficits in Scribble Deficient Mouse.
Hilal ML, Moreau MM, Racca C, Pinheiro VL, Piguel NH, Santoni MJ, Dos Santos Carvalho S, Blanc JM, Abada YK, Peyroutou R, Medina C, Doat H, Papouin T, Vuillard L, Borg JP, Rachel R, Panatier A, Montcouquiol M, Oliet SHR, Sans N

Abstract:
Planar cell polarity (PCP) signaling is well known to play a critical role during prenatal brain development; whether it plays specific roles at postnatal stages remains rather unknown. Here, we investigated the role of a key PCP-associated gene scrib in CA1 hippocampal structure and function at postnatal stages. We found that Scrib is required for learning and memory consolidation in the Morris water maze as well as synaptic maturation and NMDAR-dependent bidirectional plasticity. Furthermore, we unveiled a direct molecular interaction between Scrib and PP1/PP2A phosphatases whose levels were decreased in postsynaptic density of conditional knock-out mice. Remarkably, exposure to enriched environment (EE) preserved memory formation in CaMK-Scrib-/- mice by recovering synaptic plasticity and maturation. Thus, Scrib is required for synaptic function involved in memory formation and EE has beneficiary therapeutic effects. Our results demonstrate a distinct new role for a PCP-associated protein, beyond embryonic development, in cognitive functions during adulthood.




01/02/2015 | Development   IF 5.4
Ciliary proteins Bbs8 and Ift20 promote planar cell polarity in the cochlea.
May-Simera HL, Petralia RS, Montcouquiol M, Wang YX, Szarama KB, Liu Y, Lin W, Deans MR, Pazour GJ, Kelley MW

Abstract:
Primary cilia have been implicated in the generation of planar cell polarity (PCP). However, variations in the severity of polarity defects in different cilia mutants, coupled with recent demonstrations of non-cilia-related actions of some cilia genes, make it difficult to determine the basis of these polarity defects. To address this issue, we evaluated PCP defects in cochlea from a selection of mice with mutations in cilia-related genes. Results indicated notable PCP defects, including mis-oriented hair cell stereociliary bundles, in Bbs8 and Ift20 single mutants that are more severe than in other cilia gene knockouts. In addition, deletion of either Bbs8 or Ift20 results in disruptions in asymmetric accumulation of the core PCP molecule Vangl2 in cochlear cells, suggesting a role for Bbs8 and/or Ift20, possibly upstream of core PCP asymmetry. Consistent with this, co-immunoprecipitation experiments indicate direct interactions of Bbs8 and Ift20 with Vangl2. We observed localization of Bbs and Ift proteins to filamentous actin as well as microtubules. This could implicate these molecules in selective trafficking of membrane proteins upstream of cytoskeletal reorganization, and identifies new roles for cilia-related proteins in cochlear PCP.




11/2014 | Med Sci (Paris)   IF 0.4
[The multiple links between cilia and planar cell polarity].
Ezan J, Montcouquiol M

Abstract:
Since our seminal study in 2003, much has been written about core planar cell polarity (core PCP) signaling and the inner ear. In just a few years, and using the inner ear as a model system, our understanding of the molecular basis of this signaling pathway and how it can influence the development of tissues in mammals has increased considerably. Recently, a number of studies using various animal models of development have uncovered original relationships between the cilia and PCP, and the study of the hair cells of the inner ear has helped elucidating one of these links. In this review, we highlight the differences of PCP signaling between mammals and invertebrates. In the light of recent results, we sum up our current knowledge about PCP signaling in the mammalian cochlear epithelium and we discuss the impact of recent data in the field. We focus our attention on the interrelationship between asymmetric polarity complexes and the position of the cilium, which is essential for the establishment of the overall tissue polarity.




23/10/2014 | Cell Rep   IF 8
Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling.
Piguel NH, Fievre S, Blanc JM, Carta M, Moreau MM, Moutin E, Pinheiro VL, Medina C, Ezan J, Lasvaux L, Loll F, Durand CM, Chang K, Petralia RS, Wenthold RJ, Stephenson FA, Vuillard L, Darbon H, Perroy J, Mulle C, Montcouquiol M, Racca C, Sans N

Abstract:
The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.