title: Role of p63 and the Notch pathway in cochlea development and sensorineural deafness.
abstract: The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 (TRP63) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. Accordingly, p63 null mouse embryos show marked cochlea abnormalities, and the transactivating isoform of p63 (TAp63) protein is normally found in the organ of Corti. TAp63 transactivates hairy and enhancer of split 5 (Hes5) and atonal homolog 1 (Atoh1), components of the Notch pathway, known to be involved in cochlear neuroepithelial development. Strikingly, p63 null mice show morphological defects of the organ of Corti, with supernumerary hair cells, as also reported for Hes5 null mice. This phenotype is related to loss of a differentiation property of TAp63 and not to loss of its proapoptotic function, because cochleas in mice lacking the critical Bcl-2 homology domain (BH-3) inducers of p53- and p63-mediated apoptosis--Puma, Noxa, or both--are normal. Collectively, these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations.
authors.affiliation: Biochemistry Laboratory Istituto Dermopatico Dell'Immacolata, c/o Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Rome, Italy. alessandro.terrinoni@uniroma2.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Terrinoni
authors.forename: Valeria
authors.initials: V
authors.lastname: Serra
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bruno
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Valente
authors.forename: Elsa R
authors.initials: ER
authors.lastname: Flores
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D003051:Cochlea / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D003638:Deafness / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D004476:Ectodermal Dysplasia / Q000196:embryology / Q000235:genetics / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D051880:Receptors, Notch; D012097:Repressor Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C500943:Atoh1 protein, mouse; C489685:Hes5 protein, mouse; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; C486419:Trp63 protein, mouse