Gata3 Is a Critical Regulator of Cochlear Wiring

Abstract

Spiral ganglion neurons (SGNs) play a key role in hearing by rapidly and faithfully transmitting signals from the cochlea to the brain. Identification of the transcriptional networks that ensure the proper specification and wiring of SGNs during development will lay the foundation for efforts to rewire a damaged cochlea. Here, we show that the transcription factor Gata3, which is expressed in SGNs throughout their development, is essential for formation of the intricately patterned connections in the cochlea. We generated conditional knock-out mice in which Gata3 is deleted after SGNs are specified. Cochlear wiring is severely disrupted in these animals, with premature extension of neurites that follow highly abnormal trajectories towards their targets, as shown using in vitro neurite outgrowth assays together with time-lapse imaging of whole embryonic cochleae. Expression profiling of mutant neurons revealed a broad shift in gene expression towards a more differentiated state, concomitant with minor changes in SGN identity. Thus, Gata3 appears to serve as an “intermediate regulator” that guides SGNs through differentiation and preserves the auditory fate. As the first auditory-specific regulator of SGN development, Gata3 provides a useful molecular entry point for efforts to engineer SGNs for the restoration of hearing.

Morphological and physiological development of auditory synapses

“…However, little is known about the cues that regulate these early wiring events, though several neurotrophins, classical guidance molecules, and extracellular matrix proteins are clearly involved (Appler et al, 2011; Coate et al, 2013; Defourny et al, 2011; Yang et al, 2011a). In addition, intrinsic factors act in SGNs to influence these wiring events, with the transcription factor Gata3 playing a major role in the initiation and coordination of SGN differentiation (Appler et al, 2013; Duncan et al, 2013; Luo et al, 2013) and Prox1 ensuring that Type II SGN fibers are oriented toward the base of the cochlea (Fritzsch et al, 2010). Indeed, Type II afferents can be recognized as early as E16.5, based on their morphology, consistent with the idea that these initial guidance events are intrinsically controlled (Koundakjian et al, 2007).…”

Auditory and Vestibular Phenotypes Associated With GATA3 Mutation

“…GATA3 belongs to the GATA family of zinc finger transcription factors, which are named according to their DNA binding sequence (GATA). GATA3 plays an important role in inner ear development [2-4], and mutations affecting GATA3 are associated with HDR syndrome, which stands for hypoparathyroidism, deafness, and renal dysplasia [5-22]. It has been reported that patients with GATA3 mutations present with early-onset sensorineural hearing loss.…”

Comparative expression analysis of POU4F1, POU4F2 and ISL1 in developing mouse cochleovestibular ganglion neurons

“…In mice, neurogenesis initiates as CVG neuronal progenitors emanate from the otic placode at E9.5 and finishes at E15.5 to form the CVG, which later separates into the spiral and vestibular ganglia (Fritzsch et al, 2002; Fritzsch et al, 1999; Morsli et al, 1998). Studies have implicated the essential roles of several transcription factor genes in the development of CVG neurons, such as the bHLH genes Neurog1 (Ma et al, 1998) and Neurod1 (Kim et al, 2001; Liu et al, 2000) , and the GATA family gene Gata3 (Appler et al, 2013; Duncan and Fritzsch, 2013; Duncan et al, 2011; Economou et al, 2013; Jones and Warchol, 2009; Lawoko-Kerali et al, 2002; Lawoko-Kerali et al, 2004; Luo et al, 2013). …”