Venue: Institut François Magendie (salle de conférence)
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Meeting ID: 358 976 077 001
Passcode: oD8oL4
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Thesis supervisor: Mireille Montcouquiol
Team: Planar polarity and plasticity (Montcouquiol / Sans) – Neurocentre Magendie
Title
Loss of Multiple PDZ domain containing protein has sensory and cognitive consequences
Abstract
Multiple PDZ domain containing protein (MPDZ or MUPP1) is a large cytosolic polarity protein with thirteen PDZ domains present at the tight junction of epithelial cells and at the synapses of neurons. In both systems (epithelial and neuronal) it functions as a scaffolding protein to participate in the maturation and in the function of the cell and tissues. Genetic variations within MPDZ have been associated with various pathologies including congenital hydrocephalus with brain and eye anomalies (HYC2, OMIM #603785) or alcohol and sedative dependence. Some patients with MPDZ variants were diagnosed with sensorineural hearing loss and mild intellectual disability (ID), but these aspects received little attention. Notably, while many studies report different aspects of the gene/protein characteristics, there is no study of the consequences of the early deletion of the gene within the inner ear and the brain within the same genetic model. This thesis focuses on evaluating the structural and functional consequences of an early conditional deletion of MPDZ in the inner ear and in the brain of a mouse, in the hope of better understanding the pleiotropic effect of the deletion on some developmental mechanisms controlled by MPDZ. We generated two mice models: one with a deletion in the inner ear (MPDZear) and one with a deletion in the brain (MPDZbrain). In the MPDZear mutant, I evaluated the consequences of loss of MPDZ using hearing tests and balance vestibular test, revealing deficits in both systems. Next, I identified structural deficit domain-containings in the auditory hair cells, both in their apical and their synaptic compartments. I found a clear disruption of the hair bundle structure, consistent with a reduction and a mislocalisation of some apical surface markers, as well as a disorganization of some of the synaptic components. Functional correlates confirmed a disrupted intake of FM1-43 uptake at the hair bundle and an abnormal Ca2+ increase associated with decreased exocytosis efficiency at the synapse side of the hair cell. In the MPDZbrain mutant, while we did not identify gross anatomical deficits, our data revealed a deficits, and notably a decreased prepulse inhibition (PPI) response, typical of a disruption in sensory gating.
Taken together, these data identify a number of epithelial and synaptic disruptions in the inner ear supporting the hearing and balance deficits of our model, and further show brainspecific deficits that could participate to the sensory deficit but are also consistent with the ID observed in patients.
Jury
Pr. Paul Avan, Dr. Aziz El Amraoui, Dr. Susanna Pietropaolo, Dr. Regis Nouvian, Dr. Didier Dulon, Dr Mireille Montcouquiol