Spiral ganglion cell degeneration-induced deafness as a consequence of reduced GATA factor activity
Spiral ganglion cell degeneration-induced deafness as a consequence of reduced GATA factor activity
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DOI：
10.1111/gtc.12705
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发表时间：
2019-08-01
期刊：
影响因子：
2.1
通讯作者：
Moriguchi, Takashi
中科院分区：
文献类型：
--
作者：
Hoshino, Tomofumi;Terunuma, Tsumoru;Moriguchi, Takashi
锌指转录因子GATA2和GATA3都在发育中的内耳中表达，尽管它们在成年内耳中的重叠与不同活动尚不清楚。我们在这里发现GATA2和GATA3在耳蜗螺旋神经节细胞中共表达，并在螺旋神经节细胞和听觉神经回路的维持中起冗余作用。值得注意的是，Gata2和Gata3复合杂合突变小鼠由于凋亡增强，螺旋神经节细胞数量减少，导致进行性听力丧失。螺旋神经节细胞的减少与神经营养因子受体TrkC的表达降低有关，TrkC是螺旋神经节细胞存活的重要因素。我们进一步表明，额外携带Gata2 YAC（酵母人工染色体）的Gata2零突变体，抵消了由于Gata2完全丢失而导致的致命的造血缺陷，但未能补充新生儿螺旋神经节神经元的缺陷。此外，耳蜗特异性Gata2缺失小鼠也有更少的螺旋神经节细胞和由此产生的听力障碍。这些结果表明GATA2和GATA3在维持螺旋神经节细胞和听力方面具有冗余功能。我们提出了人类GATA2或gata3相关遗传疾病导致听力损失的可能机制。
Zinc-finger transcription factors GATA2 and GATA3 are both expressed in the developing inner ear, although their overlapping versus distinct activities in adult definitive inner ear are not well understood. We show here that GATA2 and GATA3 are co-expressed in cochlear spiral ganglion cells and redundantly function in the maintenance of spiral ganglion cells and auditory neural circuitry. Notably, Gata2 and Gata3 compound heterozygous mutant mice had a diminished number of spiral ganglion cells due to enhanced apoptosis, which resulted in progressive hearing loss. The decrease in spiral ganglion cellularity was associated with lowered expression of neurotrophin receptor TrkC that is an essential factor for spiral ganglion cell survival. We further show that Gata2 null mutants that additionally bear a Gata2 YAC (yeast artificial chromosome) that counteracts the lethal hematopoietic deficiency due to complete Gata2 loss nonetheless failed to complement the deficiency in neonatal spiral ganglion neurons. Furthermore, cochlea-specific Gata2 deletion mice also had fewer spiral ganglion cells and resultant hearing impairment. These results show that GATA2 and GATA3 redundantly function to maintain spiral ganglion cells and hearing. We propose possible mechanisms underlying hearing loss in human GATA2- or GATA3-related genetic disorders.