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Hair cells of the developing mammalian inner ear are progressively defined through cell fate restriction. This process culminates in the expression of the bHLH transcription factor  Atoh1 , which is necessary for differentiation of hair cells, but not for their specification. Loss of several genes will disrupt ear morphogenesis or arrest of neurosensory epithelia development. We previously showed in null mutants that the loss of the transcription factor,  Gata3 , results specifically in the loss of all cochlear neurosensory development. Temporal expression of  Gata3  is broad from the otic placode stage through the postnatal ear. It therefore remains unclear at which stage in development Gata3 exerts its effect. To better understand the stage specific effects of Gata3, we investigated the role of Gata3 in cochlear neurosensory specification and differentiation utilizing a LoxP targeted  Gata3  line and two Cre lines.  Foxg1 Cre ∶Gata3 f/f   mice show recombination of  Gata3  around E8.5 but continue to develop a cochlear duct without differentiated hair cells and spiral ganglion neurons. qRT-PCR data show that  Atoh1  was down-regulated but not absent in the duct whereas other hair cell specific genes such as  Pou4f3  were completely absent. In addition, while  Sox2  levels were lower in the  Foxg1 Cre :Gata3 f/f   cochlea,  Eya1  levels remained normal. We conclude that Eya1 is unable to fully upregulate  Atoh1 or Pou4f3 , and drive differentiation of hair cells without Gata3.  Pax2-Cre∶Gata3 f/f   mice show a delayed recombination of  Gata3  in the ear relative to  Foxg1 Cre :Gata3 f/f  . These mice exhibited a cochlear duct containing patches of partially differentiated hair cells and developed only few and incorrectly projecting spiral ganglion neurons. Our conditional deletion studies reveal a major role of Gata3 in the signaling of prosensory genes and in the differentiation of cochlear neurosenory cells. We suggest that Gata3 may act in combination with Eya1, Six1, and Sox2 in cochlear prosensory gene signaling.

Continued Expression of GATA3 Is Necessary for Cochlear Neurosensory Development