Tissue interactions in taste bud development

描述（由申请人提供）：味蕾以分布阵列的形式存在于舌表面上，并由将味觉信息传递到大脑的颅神经支配。近世纪来，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变化。现在许多研究表明，味蕾发育是通过不依赖神经的过程启动和进行的，在出生前很久就发生了，并且由发育中的舌头固有的细胞和分子机制控制。在小鼠中，舌味蕾位于上皮-间充质特化区，称为味觉乳头。味觉发育的第一个迹象是在妊娠中期舌表面出现味觉基板;人们认为味觉基板变形为味觉乳头，然后在出生时，从乳头上皮细胞的子集产生味蕾。然而，我们已经表明，味觉基板实际上是味蕾前体细胞（TBPcs），它只产生味蕾细胞，而不是味觉乳头。这些最近的研究结果作为我们的新模型的基础，其中TBPc诱导是味蕾发育的主要事件，而味觉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，最显著的是Wnt/β-连环蛋白和Shh;这些通路还调节味蕾和乳头发育的后期方面。到目前为止，我们已经集中在舌上皮中的Wnt和Shh的功能。然而，因为发育中的舌具有上皮和间充质隔室，并且因为味觉乳头包括被上皮包围的间充质核心，舌间充质和上皮之间的相互作用也可能是味觉周边发育的基础。在小鼠中使用新的条件分子遗传工具，我们建议探索舌间充质和上皮细胞中的Shh和Wnt功能，在精确和时间上可分离的方面的味觉器官的发展，测试总体假设：味蕾的发展是内在的舌上皮细胞，而味觉乳头的发展是由味蕾神经系统启动，需要上皮细胞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细胞诱导中的作用。目标二。确定味觉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是否是味觉细胞分化所必需的。在阐明这些机制，我们将获得重要的洞察味蕾模式和细胞补充的分子遗传调控。从长远来看，我们将利用这些进展来探索味蕾的变化如何影响健康饮食选择与有害饮食选择的味觉偏好。

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.