Department of Developmental Biology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Dev Biol. 2012 Feb 1;362(1):83-93. doi: 10.1016/j.ydbio.2011.11.019. Epub 2011 Dec 7.
The mouse inner ear develops from a simple epithelial pouch, the otocyst, with the dorsal and ventral portions giving rise to the vestibule and cochlea, respectively. The otocyst undergoes a morphological change to generate flattened saclike structures, known as outpocketings, in the dorsal and lateral regions. The semicircular canals of the vestibule form from the periphery of the outpocketings, with the central region (the fusion plate) undergoing de-epithelialization and disappearing. However, little is known of the mechanism that orchestrates formation of the semicircular canals. We now show that the area of canonical Wnt signaling changes dynamically in the dorsal otocyst during its morphogenesis. The genes for several Wnt ligands were found to be expressed in the dorsal otocyst according to specific patterns, whereas those for secreted inhibitors of Wnt ligands were expressed exclusively in the ventral otocyst. With the use of whole-embryo culture in combination with potent modulators of canonical Wnt signaling, we found that forced persistence of such signaling resulted in impaired formation both of the lateral outpocketing and of the fusion plates of the dorsal outpocketing. Canonical Wnt signaling was found to suppress Netrin1 expression and to preserve the integrity of the outpocketing epithelium. In addition, inhibition of canonical Wnt signaling reduced the size of the otocyst, likely through suppression of cell proliferation and promotion of apoptosis. Our stage-specific functional analysis suggests that strict regulation of canonical Wnt signaling in the dorsal otocyst orchestrates the process of semicircular canal formation.
小鼠内耳由一个简单的上皮囊（耳囊）发育而来，背侧和腹侧部分分别发育为前庭和耳蜗。耳囊经历形态发生变化，在背侧和外侧区域产生扁平的囊状结构，称为膨出。前庭的半规管由膨出的边缘形成，中央区域（融合板）经历去上皮化并消失。然而，协调半规管形成的机制知之甚少。我们现在表明，在其形态发生过程中，经典 Wnt 信号的区域在背侧耳囊中动态变化。根据特定的模式，发现几种 Wnt 配体的基因在背侧耳囊中表达，而 Wnt 配体的分泌抑制剂的基因则仅在腹侧耳囊中表达。通过使用整个胚胎培养并结合经典 Wnt 信号的有效调节剂，我们发现这种信号的强制持续存在导致外侧膨出和背侧膨出的融合板形成受损。经典 Wnt 信号被发现抑制 Netrin1 的表达并维持膨出上皮的完整性。此外，抑制经典 Wnt 信号降低了耳囊的大小，可能是通过抑制细胞增殖和促进细胞凋亡实现的。我们的阶段特异性功能分析表明，背侧耳囊中严格调节经典 Wnt 信号协调了半规管形成的过程。
