A Gata3–Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing (original) (raw)

Gata3 is a critical regulator of cochlear wiring

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013

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 toward 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 toward a more differentiated state, concom...

Hair cell synaptic ribbons are essential for synchronous auditory signalling

Nature, 2005

Hearing relies on faithful synaptic transmission at the ribbon synapse of cochlear inner hair cells (IHCs). At present, the function of presynaptic ribbons at these synapses is still largely unknown. Here we show that anchoring of IHC ribbons is impaired in mouse mutants for the presynaptic scaffolding protein Bassoon. The lack of active-zone-anchored synaptic ribbons reduced the presynaptic readily releasable vesicle pool, and impaired synchronous auditory signalling as revealed by recordings of exocytic IHC capacitance changes and sound-evoked activation of spiral ganglion neurons. Both exocytosis of the hair cell releasable vesicle pool and the number of synchronously activated spiral ganglion neurons co-varied with the number of anchored ribbons during development. Interestingly, ribbon-deficient IHCs were still capable of sustained exocytosis with normal Ca2+-dependence. Endocytic membrane retrieval was intact, but an accumulation of tubular and cisternal membrane profiles was ...

Current concepts in cochlear ribbon synapse formation

Synapse, 2018

In mammals, hair cells and spiral ganglion neurons (SGNs) in the cochlea together are sophisticated “sensorineural” structures that transduce auditory information from the outside world into the brain. Hair cells and SGNs are joined by glutamatergic ribbon‐type synapses composed of a molecular machinery rivaling in complexity the mechanoelectric transduction components found at the apical side of the hair cell. The cochlear hair cell ribbon synapse has received much attention lately because of recent and important findings related to its damage (sometimes termed “synaptopathy”) as a result of noise overexposure. During development, ribbon synapses between type I SGNs and inner hair cells form in the time window between birth and hearing onset and is a process coordinated with type I SGN myelination, spontaneous activity, synaptic pruning, and innervation by efferents. In this review, we highlight new findings regarding the diversity of type I SGNs and inner hair cell synapses, and t...

How Gata3 Affects Neuronal Survival in the Inner Ear

2021

Broadly speaking, Gata3 is a transcription factor involved in neurosensory specification and hair cell differentiation. Previous studies have shown that Gata3 null mutants do not develop neurons, so Gata3 appears to be necessary for neuronal survival. To better understand the role of Gata3 in spiral ganglion neurons of the inner ear, a Neurod1-cre model was used to conditionally knock out Gata3 at E9-E9.5, the timepoint when neuroblasts first begin to delaminate from the otic placode. The mutants used in this study were Nd1-cre: Gata3 f/f mutants. In situ was performed to determine gene expression within the cochlea, and immunohistochemistry was performed to label neurons as well as cell death within the cochlea. When Gata3 was conditionally knocked out and reduced in its expression, fewer neurons appear to have formed compared to the mutant and the neurons that do form lack normal projection patterns. Increased Activated Caspase3 labelling was found in the mutant compared to the co...