Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, 30322, USA.
Department of Otology and Skull Base Surgery, Eye and ENT Hospital, Fudan University, Shanghai, 200031, China.
Mol Neurobiol. 2016 Apr;53(3):1601-1612. doi: 10.1007/s12035-015-9119-0. Epub 2015 Feb 10.
Loss of vestibular hair cells is a common cause of balance disorders. Current treatment options for bilateral vestibular dysfunction are limited. During development, atonal homolog 1 (Atoh1) is sufficient and necessary for the formation of hair cells and provides a promising gene target to induce hair cell generation in the mammals. In this study, we used a transgenic mouse line to test the age and cell type specificity of hair cell induction in the postnatal utricle in mice. We found that forced Atoh1 expression in vivo can induce hair cell formation in the utricle from postnatal days 1 to 21, while the efficacy of hair cell induction is progressively reduced as the animals become older. In the utricle, the induction of hair cells occurs both within the sensory region and in cells in the transitional epithelium next to the sensory region. Within the sensory epithelium, the central region, known as the striola, is most subjective to the induction of hair cell formation. Furthermore, forced Atoh1 expression can promote proliferation in an age-dependent manner that mirrors the progressively reduced efficacy of hair cell induction in the postnatal utricle. These results suggest that targeting both cell proliferation and Atoh1 in the utricle striolar region may be explored to induce hair cell regeneration in mammals. The study also demonstrates the usefulness of the animal model that provides an in vivo Atoh1 induction model for vestibular regeneration studies.
前庭毛细胞的丧失是平衡障碍的常见原因。目前双侧前庭功能障碍的治疗选择有限。在发育过程中，Atoh1 同源物 1（Atoh1）对于毛细胞的形成是充分和必要的，并为诱导哺乳动物毛细胞生成提供了一个有前途的基因靶点。在这项研究中，我们使用转基因小鼠系来测试在出生后小鼠的前庭中毛细胞诱导的年龄和细胞类型特异性。我们发现，体内强制表达 Atoh1 可以在出生后 1 至 21 天诱导前庭中的毛细胞形成，而随着动物年龄的增长，毛细胞诱导的效果逐渐降低。在前庭中，毛细胞的诱导发生在感觉区域内和感觉区域旁边的过渡上皮细胞中。在感觉上皮中，称为条纹的中央区域最容易诱导毛细胞形成。此外，强制表达 Atoh1 可以以一种与出生后前庭中毛细胞诱导效果逐渐降低相吻合的方式促进增殖。这些结果表明，靶向前庭条纹区域的细胞增殖和 Atoh1 可能被探索用于诱导哺乳动物的毛细胞再生。该研究还证明了动物模型的有用性，该模型为前庭再生研究提供了体内 Atoh1 诱导模型。
