Tissue interactions in taste bud development

描述（由申请人提供）：味蕾分布在舌头表面，并受脑神经支配，将味觉信息传递给大脑。近一个世纪以来，味蕾被认为是由胚胎发育后期的神经诱导的。然而，在过去的十年里，这种观点发生了巨大的转变。现在的大量研究表明，味蕾的发育是通过与神经无关的过程启动和进行的，发生在出生前很久，并且受到正在发育的舌头固有的细胞和分子机制的控制。在小鼠中，舌味蕾存在于上皮间质特化中，称为味觉乳头。味觉发育的第一个迹象是在妊娠中期舌头表面味觉基板的出现。据推测，味觉基板会演变成味觉乳头，然后在出生时，乳头上皮细胞的子集会产生味蕾。然而，我们已经证明，味基板实际上是味蕾前体细胞（TBPc），它只产生味蕾细胞，而不产生味乳头。这些最近的发现是我们新模型的基础，其中 TBPc 诱导是味蕾发育的主要事件，而味乳头的形成是对新诱导的 TBPc 发出的信号的响应。许多信号通路参与 TBPcs 的诱导，其中最突出的是 Wnt/ss-catenin 和 Shh；这些途径还调节味蕾和乳头发育的后期方面。迄今为止，我们主要研究 Wnt 和 Shh 在舌上皮中的功能。然而，由于发育中的舌头同时具有上皮和间质室，并且味觉乳头包含被上皮包围的间质核心，因此舌间质和上皮之间的相互作用也可能是味觉外围发育的基础。使用小鼠中新可用的条件分子遗传工具，我们建议在味觉器官发育的精确和时间可分离方面探索舌间充质和上皮中的Shh和Wnt功能，测试总体假设：味蕾的发育是舌上皮固有的，而味乳头发育是由味蕾前体启动的，并且需要上皮和间充质之间的相互作用。目标 1. 明确舌上皮和间充质在味蕾前体诱导中的作用。目标 2. 确定味乳头的形态发生是否需要接收来自味蕾前体的信号。目标 3. 测试味蕾前体的自分泌信号传导是否是味觉细胞分化所必需的。在阐明这些机制的过程中，我们将获得对味蕾模式和细胞补体的分子遗传调控的重要见解。从长远来看，我们将利用这些进展来探索味蕾变化如何影响健康与有害饮食选择背后的味觉偏好。

DESCRIPTION (provided by applicant): Taste buds are found in a distributed array on the tongue surface, and are innervated by cranial nerves that convey taste information to the brain. For nearly a century, taste buds were thought to be induced by nerves late in embryonic development. Over the past decade, however, this view has shifted dramatically. A host of studies now indicate that taste bud development is initiated and proceeds via processes that are nerve- independent, occur long before birth, and are governed by cellular and molecular mechanisms intrinsic to the developing tongue. In mice, lingual taste buds reside in epithelial-mesenchymal specializations, termed taste papillae. The first indication of taste development is the appearance of taste placodes in the tongue surface at midgestation; it has been assumed that taste placodes morph into taste papillae, which then, around birth, produce taste buds from a subset of papilla epithelial cells. However, we have shown that taste placodes are actually taste bud precursor cells (TBPcs), which give rise to taste bud cells only, and not to taste papillae. These recent findings serve as the basis for our new model, one in which TBPc induction is the primary event in taste bud development, while taste papillae form in response to signals emitted from newly induced TBPcs. A number of signaling pathways are involved in the induction of TBPcs, most prominently Wnt/ss-catenin and Shh; these pathways also regulate later aspects of taste bud and papilla development. To date, we have focused on the functions of Wnt and Shh in lingual epithelium. However, because the developing tongue has both epithelial and mesenchymal compartments, and because taste papillae comprise a mesenchymal core surrounded by epithelium, interactions between lingual mesenchyme and epithelium also likely underlie development of the taste periphery. Using newly available conditional molecular genetic tools in mice, we propose to explore Shh and Wnt function in lingual mesenchyme and epithelium during precise and temporally separable aspects of taste organ development, testing the overarching hypothesis that: Development of taste buds is intrinsic to lingual epithelium, while taste papilla development is initiated by taste bud precursos and requires interactions between epithelium and mesenchyme. Aim 1. Define the roles of lingual epithelium and mesenchyme in the induction of taste bud precursors. Aim 2. Determine if morphogenesis of taste papillae requires receipt of signals from taste bud precursors. Aim 3. Test if autocrine signaling by taste bud precursors is required for taste cell differentiation. In elucidating these mechanisms, we will gain crucial insight into molecular genetic regulation of taste bud pattern and cell complement. In the long term, we will leverage these advances in our understanding to explore how taste bud variation influences taste preferences underlying healthy versus detrimental dietary choices.