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Rodriguez Hernandez, Laura (2013) Studies of intercellular Ca2+ signaling and gap-junction coupling in the developing cochlea of mouse models affected by congenital hearing loss. [Tesi di dottorato]

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Abstract (inglese)

Connexin 26 (Cx26) and connexin 30 (Cx30) form gap junction channels that allow the intercellular diffusion of the Ca2+ mobilizing second messenger IP3. They also form hemichannels that release ATP from the endolymphatic surface of cochlear supporting and epithelial cells. Released ATP in turn activates G-protein coupled P2Y2 and P2Y4 receptors, PLC-dependent generation of IP3, release of Ca2+ from intracellular stores, permitting the regenerative propagation of intercellular Ca2+ signals.
In the course of this work, we found that cochlear non-sensory cells of the greater and lesser epithelial ridge (GER and LER, respectively) share the same PLC- and IP3R-dependent signal transduction cascade activated by ATP. In addition, we demonstrated that ATP-dependent Ca2+ signaling activity in cochlear non-sensory cells is spatially graded from the apex to the base of the cochlea during the first postnatal week. Ca2+ signaling under these conditions depends on inositol-1,4,5-trisphosphate generation from phospholipase C (PLC)-dependent hydrolysis of PI(4,5)P(2). Thus we analyzed mice with defective expression of PIPKIγ and found that (i) this enzyme is essential for the acquisition of hearing; (ii) it is primarily responsible for the synthesis of the receptor-regulated PLC-sensitive PI(4,5)P(2) pool in the cell syncytia that supports auditory hair cells and; (iii) spatially graded impairment of the PIP2-IP3-Ca2+ signaling pathway in cochlear non-sensory cells affects the level of gap junction coupling. Vice versa, we found defective gap junction coupling and intercellular IP3-dependent Ca2+ signaling the cochlea of mice with targeted ablation Cx26 or Cx30, as well as in mice knock in for a point mutation (Cx30T5M) associated with human congenital deafness. Altogether, our findings link bidirectionally defective hearing acquisition to Ca2+ signaling impairment and decreased biochemical coupling in the developing cochlea. Transduction of connexin deficient cochlear cultures with a bovine adeno associated virus vectors encoding Cx26 or Cx30 restored protein expression, rescued both gap junction coupling and Ca2+ signaling.
Based on this work, we conclude that in vivo connexin gene delivery to the inner ear is a route worth exploring to rescue hearing function in mouse models of deafness and, in future, may lead to the development of therapeutic interventions in humans.

Abstract (italiano)

La connessina 26 (Cx26) e la connessina 30 (Cx30) formano canali giunzionali che permettono la diffusione intercellulare del secondo messaggero IP3 e la mobilitazione del Ca2+. Le connessine formano anche emicanali che rilasciano ATP dalla superficie endolinfatica delle cellule di supporto ed epiteliali della coclea. L’ATP rilasciato attiva a sua volta recettori P2Y2 e P2Y4 accoppiati a proteina G, la generazione di IP3 dipendente da fosfolipasi C (PLC) e il rilascio di Ca2+ dai depositi intracellulari, permettendo la propagazione rigenerativa dei segnali Ca2+ intercellulari.
Nel corso di questo lavoro, abbiamo osservato che le cellule cocleari non-sensoriali che compongono il ‘greater and lesser epithelial ridge’ (GER e LER, rispettivamente) condividono la stessa cascata di trasduzione del segnale attivato da ATP dipendente da PLC e IP3R. Inoltre, abbiamo dimostrato che l’attività dei segnali Ca2+ ATP-dipendente nelle cellule cocleari non-sensoriale è spazialmente ordinata dall'apice alla base della coclea durante la prima settimana postnatale. Il segnale di Ca2+ in queste condizioni dipende della generazione del’inositolo-1,4,5-trifosfato a partire dell’idrolisi di PI(4,5)P(2) dipendente da PLC. Abbiamo quindi analizzato dei topi con espressione difettosa di PIPKIγ e abbiamo mostrato che (i) tale enzima è essenziale per l'acquisizione dell’udito, (ii) è responsabile principalmente della sintesi di pool di PI(4,5)P(2) regolati da recettore e sensibili a PLC nei sincizi cellulari che fanno da supporto alle cellule ciliate uditive, e che (iii) la diminuzione spaziale della via di segnalazione PIP2-IP3- Ca2+ in cellule cocleari non-sensoriale influenza il livello di accoppiamento delle giunzioni cellulari. Viceversa, abbiamo trovato un accoppiamento difettoso delle giunzioni cellulari e dei segnali di Ca2+ intercellulari IP3-dipendenti della coclea di topi con mutazione puntuali delle Cx26 o Cx30, così come nei topi knock in per una mutazione puntiforme (Cx30T5M) associata a sordità. Complessivamente, i nostri risultati collegano una difettosa acquisizione uditiva all’insufficienza di segnalazione di Ca2+ e a una diminuzione nell’accoppiamento biochimico nella coclea in via di sviluppo. La trasduzione di culture di coclea con un deficit di connessine con dei vettori di virus adeno-associato bovino codificanti la Cx26 o Cx30 ristabiliscono l’espressione della proteina, e la funzionalità delle gap junctions e dei segnali di Ca2+.
Sulla base di questo lavoro, si può concludere che l’applicazione in vivo dei geni per le connessine nell'orecchio interno è un percorso che vale la pena di esplorare per ristabilire la funzione uditiva in modelli murini di sordità e che, in futuro, potrebbe portare allo sviluppo di interventi terapeutici nell’uomo.

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Tipo di EPrint:Tesi di dottorato
Relatore:Mammano, Fabio
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > BIOSCIENZE E BIOTECNOLOGIE > NEUROBIOLOGIA
Data di deposito della tesi:29 Gennaio 2013
Anno di Pubblicazione:29 Gennaio 2013
Parole chiave (italiano / inglese):gap-junctions, calcium signaling, cochlea, deafness
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Dipartimenti > Dipartimento di Fisica e Astronomia "Galileo Galilei"
Codice ID:5721
Depositato il:10 Ott 2013 13:04
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