Duncan Jeremy S, Lim Kim-Chew, Engel James D, Fritzsch Bernd
Department of Biology, University of Iowa, Iowa, USA.
Int J Dev Biol. 2011;55(3):297-303. doi: 10.1387/ijdb.103178jd.
Haploinsufficiency of Gata3 causes hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome in mice and humans. Gata3 null mutation leads to early lethality around embryonic day (E)11.5, but catecholamine precursor administration can rescue Gata3 null mutants to E16.5. At E11.5, GATA3 deficiency results in the development of an empty otocyst with an endolymphatic duct. However, using rescued mice we found that some morphogenesis and neurosensory development is possible in the ear without Gata3. Extending previous studies, we find that at E16.5, Gata3 mutant inner ears can undergo partial morphogenesis and develop an endolymphatic duct, a utricular and saccular recess, and a shortened cochlear duct. In addition to the obvious morphogenic aberrations, these studies demonstrate that a subset of neurons develop and connect a fragmented sensory patch of MYO7A-positive hair cells to the vestibular nuclei of the brainstem. In situ hybridization studies reveal altered expression of several transcription factors relevant to ear development and we hypothesize that this may relate to the observed dysmorphia and restricted neurosensory development. While a cochlear duct can form, there is no concurrent cochlear neurosensory development, observations consistent with specific hearing defects encountered by HDR patients and mice with Gata3-associated expression alterations. Gata3 null mutant phenocopies the otic maldevelopment (cochlear duct formation in the absence of neurosensory development) seen in Foxg1cre mediated conditional deletion of microRNA processing enzyme, Dicer1. Finally, while GATA3 is expressed in the developing vestibulo-cochlear efferent (VCE) neurons, and its absence in the null mutants disrupts VCE projections to the ear, loss of GATA3 does not affect VCE progenitor cell migration.
Gata3单倍剂量不足在小鼠和人类中会导致甲状旁腺功能减退、耳聋和肾发育异常（HDR）综合征。Gata3基因敲除突变会导致胚胎期（E）约11.5天左右出现早期致死性，但给予儿茶酚胺前体可使Gata3基因敲除突变体存活至E16.5。在E11.5时，GATA3缺乏会导致形成一个带有内淋巴管的空耳囊。然而，利用挽救后的小鼠，我们发现没有Gata3时耳朵仍有可能进行一些形态发生和神经感觉发育。扩展先前的研究，我们发现，在E16.5时，Gata3突变体的内耳可进行部分形态发生，并发育出内淋巴管、椭圆囊和球囊隐窝以及缩短的耳蜗管。除了明显的形态发生畸变外，这些研究还表明，一部分神经元发育并将MYO7A阳性毛细胞的碎片化感觉斑与脑干的前庭核连接起来。原位杂交研究揭示了几种与耳朵发育相关的转录因子表达发生改变，我们推测这可能与观察到的畸形和受限的神经感觉发育有关。虽然耳蜗管可以形成，但同时没有耳蜗神经感觉发育，这一观察结果与HDR患者和具有Gata3相关表达改变的小鼠所出现的特定听力缺陷一致。Gata3基因敲除突变体模拟了在Foxg1cre介导的微小RNA加工酶Dicer1条件性缺失中所见的耳发育异常（在没有神经感觉发育的情况下形成耳蜗管）。最后，虽然GATA3在发育中的前庭蜗传出（VCE）神经元中表达，其在基因敲除突变体中的缺失会破坏VCE向耳朵的投射，但GATA3的缺失并不影响VCE祖细胞的迁移。
