Tissue interactions in taste bud development

描述(申请人提供)：味蕾分布在舌面上，由脑神经支配，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，在过去十年里，这种观点发生了戏剧性的转变。现在许多研究表明，味蕾的发育是通过不依赖神经的过程启动和进行的，早在出生之前就发生了，并受到舌头发育中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充质特化中，称为味觉乳头。味觉发育的第一个迹象是孕中期舌面上出现味觉安慰剂；人们一直认为味觉安慰剂会转变为味觉乳头，然后在出生前后，味觉乳头上皮细胞子集产生味蕾。然而，我们已经证明，味觉安慰剂实际上是味蕾前体细胞，它只产生味蕾细胞，而不产生味觉乳头。这些最新的发现为我们的新模型奠定了基础，在这个模型中，TBPc的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TBPcs发出的信号的响应。许多信号通路参与了TBPcs的诱导，最突出的是Wnt/ss-catenin和Shh；这些通路还调节味蕾和乳突发育的后期。到目前为止，我们主要关注Wnt和Shh在舌上皮细胞中的功能。然而，由于发育中的舌体既有上皮区又有间充质区，而且味觉乳头由一个被上皮包围的间充质核组成，舌间充质和上皮之间的相互作用也可能是味觉外周发育的基础。利用在小鼠身上新获得的条件分子遗传学工具，我们建议探索舌间充质和舌间充质上皮在味觉器官发育的精确和时间上可分离的方面的Shh和Wnt的功能，验证了最重要的假设：味蕾的发育是舌上皮所固有的，而味乳头的发育是由味蕾前体启动的，需要上皮和间充质之间的相互作用。目的1.明确舌上皮和间充质在味蕾前体诱导中的作用。目的2.确定味觉乳头的形态发生是否需要接受味蕾前体的信号。目的3.检测味蕾前体的自分泌信号是否参与味觉细胞的分化。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，我们将利用我们理解中的这些进步来探索味蕾变化如何影响潜在的健康与有害饮食选择的口味偏好。

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.