TY - JOUR T1 - Remodeling of the inner hair cell microtubule meshwork in a mouse model of auditory neuropathy AUNA1 JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0295-16.2016 SP - ENEURO.0295-16.2016 AU - Clément Surel AU - Marie Guillet AU - Marc Lenoir AU - Jérôme Bourien AU - Gaston Sendin AU - Willy Joly AU - Benjamin Delprat AU - Marci M. Lesperance AU - Jean-Luc Puel AU - Régis Nouvian Y1 - 2016/12/13 UR - http://www.eneuro.org/content/early/2016/12/13/ENEURO.0295-16.2016.abstract N2 - Auditory neuropathy 1 (AUNA1) is a form of human deafness resulting from a point mutation in the 5’ untranslated region of the Diaphanous homolog 3 (DIAPH3) gene. Notably, the DIAPH3 mutation leads to the overexpression of the DIAPH3 protein, a formin family member involved in cytoskeleton dynamics. Through study of diap3-overexpressing transgenic (Tg) mice, we examine in further detail the anatomical, functional and molecular mechanisms underlying AUNA1. We identify diap3 as a component of the hair cells apical pole in wild-type mice. In the diap3-overexpressing Tg mice, which show a progressive threshold shift associated with a defect in inner hair cells (IHCs), the neurotransmitter release and potassium conductances are not affected. Strikingly, the overexpression of diap3 results in a selective and early-onset alteration of the IHC cuticular plate. Molecular dissection of the apical components revealed that the microtubule meshwork first undergoes aberrant targeting into the cuticular plate of Tg IHCs, followed by collapse of the stereociliary bundle, with eventual loss of the IHC capacity to transmit incoming auditory stimuli.Significance Statement: The mutation in the Diaphanous homolog 3 gene, which leads to overexpression of diap3 protein, underlies the human deafness called auditory neuropathy 1 (AUNA1). While diap3 is known to regulate the cytoskeleton, the signaling cascade operating in AUNA1 is still unclear. Using a transgenic mouse model of AUNA1, which overexpresses diap3, we show that microtubules accumulate at the apical pole of the auditory sensory cells, the inner hair cells. The microtubule network remodeling is followed by the anatomical alteration of the mechano-transduction apparatus, which could explain the failure to transduce acoustic stimuli into neural message. Altogether, this study suggests that a massive microtubule remodeling occurs in the mouse model of AUNA1. ER -