Biology Department, Texas A&M University, College Station, TX 77843-3258, USA.
Dev Biol. 2011 Oct 1;358(1):113-21. doi: 10.1016/j.ydbio.2011.07.019. Epub 2011 Jul 23.
Atoh1 is required for differentiation of sensory hair cells in the vertebrate inner ear. Moreover, misexpression of Atoh1 is sufficient to establish ectopic sensory epithelia, making Atoh1 a good candidate for gene therapy to restore hearing. However, competence to form sensory epithelia appears to be limited to discrete regions of the inner ear. To better understand the developmental factors influencing sensory-competence, we examined the effects of misexpressing atoh1a in zebrafish embryos under various developmental conditions. Activation of a heat shock-inducible transgene, hs:atoh1a, resulted in ectopic expression of early markers of sensory development within 2h, and mature hair cells marked by brn3c:GFP began to accumulate 9h after heat shock. The ability of atoh1a to induce ectopic sensory epithelia was maximal when activated during placodal or early otic vesicle stages but declined rapidly thereafter. At no stage was atoh1a sufficient to induce sensory development in dorsal or lateral non-sensory regions of the otic vesicle. However, co-misexpression of atoh1a with fgf3, fgf8 or sox2, genes normally acting in the same gene network with atoh1a, stimulated sensory development in all regions of the otic vesicle. Thus, expression of fgf3, fgf8 or sox2 strongly enhances competence to respond to Atoh1.
Atoh1 对于脊椎动物内耳感觉毛细胞的分化是必需的。此外，Atoh1 的异位表达足以建立异位感觉上皮，使 Atoh1 成为恢复听力的基因治疗的良好候选物。然而，形成感觉上皮的能力似乎仅限于内耳的离散区域。为了更好地了解影响感觉能力的发育因素，我们在各种发育条件下检查了在斑马鱼胚胎中异位表达 atoh1a 的影响。热休克诱导型转基因 hs:atoh1a 的激活导致在 2 小时内出现感觉发育的早期标志物的异位表达，并且在热休克后 9 小时开始积累由 brn3c:GFP 标记的成熟毛细胞。当在膜性器官或早期耳泡阶段激活时，atoh1a 诱导异位感觉上皮的能力最大，但此后迅速下降。在没有阶段，atoh1a 足以诱导耳泡的背侧或侧部非感觉区域的感觉发育。然而，与 fgf3、fgf8 或 sox2 共同异位表达，这些基因通常与 atoh1a 在相同的基因网络中起作用，可刺激耳泡的所有区域的感觉发育。因此，fgf3、fgf8 或 sox2 的表达强烈增强了对 Atoh1 的反应能力。
