Gata3 is a critical regulator of cochlear wiring.
Gata3 is a critical regulator of cochlear wiring.
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DOI：
10.1523/jneurosci.4703-12.2013
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发表时间：
2013-02-20
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影响因子：
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通讯作者：
Goodrich LV
中科院分区：
文献类型：
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作者：
Appler JM;Lu CC;Druckenbrod NR;Yu WM;Koundakjian EJ;Goodrich LV
螺旋神经节神经元（sgn）在听力中起着关键作用，通过快速和忠实地将信号从耳蜗传递到大脑。确定在发育过程中确保sgn的正确规范和连接的转录网络将为重新连接受损耳蜗的努力奠定基础。在这里，我们发现转录因子Gata3在sgn的整个发育过程中表达，对于耳蜗中复杂模式连接的形成至关重要。我们生成了条件敲除小鼠，其中在sgn被指定后Gata3被删除。这些动物的耳蜗线路被严重破坏，神经突的过早延伸遵循高度异常的目标轨迹，如体外神经突生长测定和整个胚胎耳蜗的延时成像所示。突变神经元的表达谱揭示了基因表达向更分化状态的广泛转变，同时伴有SGN身份的微小变化。因此，Gata3似乎作为一种“中间调节剂”，引导sgn分化并保持听觉命运。Gata3作为SGN发育的首个听觉特异性调节因子，为设计SGN以恢复听力提供了一个有用的分子切入点。
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.