Raft Steven, Koundakjian Edmund J, Quinones Herson, Jayasena Chathurani S, Goodrich Lisa V, Johnson Jane E, Segil Neil, Groves Andrew K
Gonda Department of Cell and Molecular Biology, House Ear Institute, 2100 West 3rd Street, Los Angeles CA 90057, USA.
Development. 2007 Dec;134(24):4405-15. doi: 10.1242/dev.009118.
Temporal and spatial coordination of multiple cell fate decisions is essential for proper organogenesis. Here, we define gene interactions that transform the neurogenic epithelium of the developing inner ear into specialized mechanosensory receptors. By Cre-loxP fate mapping, we show that vestibular sensory hair cells derive from a previously neurogenic region of the inner ear. The related bHLH genes Ngn1 (Neurog1) and Math1 (Atoh1) are required, respectively, for neural and sensory epithelial development in this system. Our analysis of mouse mutants indicates that a mutual antagonism between Ngn1 and Math1 regulates the transition from neurogenesis to sensory cell production during ear development. Furthermore, we provide evidence that the transition to sensory cell production involves distinct autoregulatory behaviors of Ngn1 (negative) and Math1 (positive). We propose that Ngn1, as well as promoting neurogenesis, maintains an uncommitted progenitor cell population through Notch-mediated lateral inhibition, and Math1 irreversibly commits these progenitors to a hair-cell fate.
多种细胞命运决定的时空协调对于正常器官发生至关重要。在此，我们定义了将发育中的内耳神经上皮转化为特殊机械感觉受体的基因相互作用。通过Cre-loxP命运图谱，我们表明前庭感觉毛细胞源自内耳先前的神经源性区域。相关的bHLH基因Ngn1（Neurog1）和Math1（Atoh1）分别是该系统中神经和感觉上皮发育所必需的。我们对小鼠突变体的分析表明，Ngn1和Math1之间的相互拮抗作用调节了耳朵发育过程中从神经发生到感觉细胞产生的转变。此外，我们提供证据表明，向感觉细胞产生的转变涉及Ngn1（负向）和Math1（正向）不同的自调节行为。我们提出，Ngn1除了促进神经发生外，还通过Notch介导的侧向抑制维持未分化的祖细胞群体，则Math1不可逆地使这些祖细胞定向分化为毛细胞命运。
