| Nat Commun IF 12.1 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*
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.
| Cereb Cortex IF 6.6 Activity-Dependent Neuroplasticity Induced by an Enriched Environment Reverses Cognitive Deficits in Scribble Deficient Mouse
Hilal ML, Moreau MM, Racca C, Pinheiro V, Piguel N, Santoni M-J, Dos santos carvalho S, Blanc JM, Abada Y, Peyroutou R, Medina C, Doat H, Papouin T, Vuillard L, Borg JP, Rachel R, Panatier A, Montcouquiol M*, Oliet SHR*, Sans N*
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.