Molecular mechanisms of taste bud development.

描述(申请人提供)：味觉外围包括由不同的脑神经支配的味蕾的分布阵列。近年来，关于这一系统的萌芽发展的理论经历了根本性的修改。以前，味蕾被认为是由味觉神经生长中的冷漠上皮诱导而来；但新的结果表明，味蕾发育的早期事件发生在完全没有神经支配的情况下，这又提出了味蕾如何发育的新问题。我们现在建议通过利用小鼠模型系统的优秀分子遗传学来研究这个问题。在老鼠身上，舌头味蕾仅限于乳头，乳头在怀孕中期形成，可能含有味蕾祖细胞；然而，味蕾直到出生后才真正出现。两个信号因子(Sonic Hedgehog[Shh]和骨形态发生蛋白[BMPs])在乳头状上皮细胞亚群中表达，这两个通路都影响小鼠的味觉发育。我们的初步数据表明，表达Shh的细胞可能是味蕾干细胞。我们的最新发现表明，在味觉器官发育过程中，还有另一个至关重要的信号系统--Wnt通路，因为胚胎舌头中Wnt信号的获得或丢失显著影响乳头。已知这3个信号通路(Wnt、Shh和BMP)的相互作用可以驱动许多其他上皮特化的发育，包括毛发、羽毛和牙齿，但它们在味觉器官发育中的确切作用尚不清楚。通过对早期味觉器官发育的神经独立观点和分子遗传学方法，我们现在准备找出控制这一重要感觉系统发育的分子机制。在以下三个目标中，我们将检验总体假设：味蕾起源于表达Shh的胚胎干细胞，其发育受到Wnt、Shh和BMP途径相互作用的调控。目的1：确定表达Shh的胚胎味蕾细胞是否是味蕾干细胞。目的2：确定WNTS如何与BMP和Shh相互作用来调节味觉器官的发育。目的3：检测上皮性Wnt信号是否足以促进味觉器官的发育。这些目标的成功实现对于与味觉功能相关的人类健康问题以及更广泛地提高对胚胎发育及其错误调控的认识都是重要的。

DESCRIPTION (provided by applicant): The taste periphery comprises a distributed array of taste buds innervated by distinct cranial nerves. In recent years, theories of the embryonic development of this system have undergone radical revision. Previously, taste buds were thought to be induced from indifferent epithelium by in growth of taste nerves; but new results demonstrate that early events in taste bud development occur before, and in the total absence of, innervation, raising anew questions of how taste buds develop. We now propose to examine this problem by taking advantage of the excellent molecular genetics of the mouse model system. In mice, lingual taste buds are restricted to papillae, which form by mid-gestation and likely contain taste bud progenitors; yet taste buds proper do not appear until postnatal stages. Two signaling factors (Sonic Hedgehog [Shh] and Bone Morphogenetic Proteins [BMPs]) are expressed in a subset of papillary epithelial cells, and both pathways influence murine taste development. Our preliminary data suggest that the Shh- expressing cells may be taste bud stem cells. And our newest findings implicate yet another, crucial signaling system, the Wnt pathway, in taste organ development, as gain or loss of Wnt signaling in embryonic tongues significantly affects papillae. Interactions of these 3 signaling pathways (Wnt, Shh and BMP) are known to drive development of many other epithelial specializations, including hair, feather and teeth, but their precise roles in taste organ development are unknown. With a nerve-independent view of early taste organ development, and a molecular genetic approach, we are now poised to work out the molecular mechanisms governing development of this vital sensory system. In the following 3 aims, we will test the overall hypothesis that: Taste buds originate from embryonic Shh-expressing stem cells whose development is regulated by interactions of the Wnt, Shh and BMP pathways. Aim 1: Ascertain whether embryonic Shh-expressing taste placode cells are taste bud stem cells. Aim 2: Determine how Wnts interact with BMP and Shh to regulate taste organ development. Aim 3: Test if epithelial Wnt signaling is sufficient for taste organ development. Successful completion of these aims is important for issues of human health related to taste function, as well as more generally to enhance knowledge of embryonic development and its misregulation.