Taste organs: formation and regulation

味觉器官：形成和调节

基本信息

批准号：
8598468
负责人：
Hongxiang Liu
金额：
$ 37.29万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598468
关键词：
ACVR1 gene Address Biological Assay Biological Models Biology Bone Morphogenetic Proteins Cell Differentiation process Cell Lineage Cells Cephalic Chemicals Data Derivation procedure Development Elements Embryo Epithelial Epithelial Cells Epithelium Fungiform Papilla Genetic Genetic Recombination Goals Homeostasis In Vitro Ingestion Knock-out Knowledge Label Lead Life Link Location Maintenance Mammals Maps Mediating Mesenchymal Mesenchymal Differentiation Mesenchyme Midbrain structure Modification Molecular Monitor Mus Neural Crest Neural Crest Cell Neuraxis Nutrient Organ Pathway interactions Pattern Phenotype Primordium Quality of life Regulation Role Sensory Signal Pathway Signal Transduction Staging Stimulus Taste Bud Cell Taste Buds Taste Disorders Taste Perception Techniques Tissue Recombination Tissues Tongue Transgenic Mice base bone morphogenetic protein receptor type I bone morphogenetic protein receptors cell motility cell type density early embryonic stage hindbrain in vivo migration mouse model novel precursor cell public health relevance receptor relating to nervous system tongue papilla tool

项目摘要

DESCRIPTION (provided by applicant): Taste bud cells, the sensory end organs that transduce chemical stimuli into neural signals conveyed to the central nervous system, reside in taste papillae in the mammalian tongue. Therefore, taste papillae host the epithelium that will differentiate to include taste bud cells. However, the field of taste biology lacks a complete understanding of: (1) what constitutes possible taste cell precursors in developing papillae; (2) how and when the precursors differentiate in lingual epithelium to acquire taste papilla and taste bud cell phenotypes; and (3) how and via what factors the underlying mesenchyme signals to tongue epithelium in papilla and taste bud development. Our preliminary data on neural crest (NC) derived cell distributions in lingual epithelium, and of phenotypic alterations of tongue and taste papillae induced by genetic modifications in mesenchymal NC derived cells, suggest neural crest contributions to both epithelium and mesenchyme in the formation of taste organs. Cre- mediated, tissue-specific, genetic labeling and modifications provide powerful tools for these cell lineage assays and functional analyses. Two well-characterized transgenic mouse lines for NC assays, Wnt1-Cre and P0-Cre, are used. We have found that: (1) In tongue epithelium, both Wnt1-Cre and P0-Cre labeled NC derived cells are seen including taste papillae and taste buds (abundant in P0-Cre, infrequent in Wnt1-Cre) suggesting a potential NC derivation of taste cells which leads to a new concept in the field. P0-Cre labeled cells are first distributed in single, scattered elements at early stages to a clustered pattern later in taste papillae and taste buds. We propose that the single, scattered P0-Cre labeled epithelial cells are NC precursors and these will undergo cell differentiation to specific cell types in taste papillae and taste buds. (2) In tongue mesenchyme, Wnt1-Cre labeled NC derived cells are closely associated with taste papillae and taste buds. Wnt1-Cre driven, conditional genetic modifications of type I receptors Alk2 and Alk3 for bone morphogenetic proteins (BMPs) significantly alter the tongue, taste papilla and taste bud formation and maintenance in a level-, stage- and receptor-specific manner. This suggests that BMP signaling in tongue mesenchyme, via distinct receptors, interacts with the overlying epithelium for different roles in the development of tongue, taste papillae and taste buds. The proposed studies will address fundamental issues about formation of the taste papilla organ, using modern techniques (Cre-mediated genetic modifications) and combination of in vivo and in vitro studies. Our goals are to: (Aim 1) demonstrate the optimal stage (1a) and primary cranial region (midbrain or hindbrain) (1b) of NC cell migration into the epithelium of tongue primordium; when and how many these cells differentiate in lingual epithelium to acquire specific cell phenotypes (1c); what types and proportions of taste bud cells are derived from NC (1d); (Aim 2) characterize how the BMP signaling in tongue mesenchymal NC derived cells, via distinct type I receptors (ALK2 and ALK3), interacts with the overlying epithelium in the development and maintenance of tongue, taste papillae and taste buds, with genetic modifications to (2a) down-regulate BMP signaling activity with Wnt1-Cre driven conditional knockout of Alk2 or Alk3; and (2b) up-regulate BMP signaling with Wnt1-Cre driven conditional constitutive activation of each receptor. Overall, the proposed studies for demonstration of cell origin, differentiation and mesenchymal interactions in taste papillae and taste buds will contribute to understanding development of the taste organ and will bring new information and novel perspectives to the field for neural crest contributions to taste papillae and taste bud cells.

描述（由申请人提供）：味蕾细胞是一种将化学刺激转变成传送至中枢神经系统的神经信号的感觉末端器官，存在于哺乳动物舌头的味觉乳头中。因此，味乳头承载着将分化为包括味蕾细胞的上皮。然而，味觉生物学领域缺乏对以下方面的完整理解：（1）发育乳头中可能的味觉细胞前体是由什么构成的； (2)前体细胞如何以及何时在舌上皮中分化以获得味乳头和味蕾细胞表型； (3)底层间质如何以及通过什么因素向乳头和味蕾发育中的舌上皮发出信号。我们关于舌上皮中神经嵴 (NC) 衍生细胞分布的初步数据，以及间充质 NC 衍生细胞中基因修饰诱导的舌头和味觉乳头表型改变的初步数据表明，神经嵴对上皮和间质在味觉器官形成中的贡献。 Cre介导的、组织特异性的、基因标记和修饰为这些细胞谱系测定和功能分析提供了强大的工具。使用两个用于 NC 测定的充分表征的转基因小鼠品系：Wnt1-Cre 和 P0-Cre。我们发现：（1）在舌上皮中，可以看到 Wnt1-Cre 和 P0-Cre 标记的 NC 衍生细胞，包括味觉乳头和味蕾（P0-Cre 丰富，Wnt1-Cre 不常见），表明潜在的 NC 衍生味觉细胞，这导致了该领域的一个新概念。首先是 P0-Cre 标记的细胞早期阶段以单一、分散的元素分布，后来在味乳头和味蕾中以簇状分布。我们认为单个分散的 P0-Cre 标记上皮细胞是 NC 前体细胞，这些细胞将在味乳头和味蕾中经历细胞分化，形成特定的细胞类型。 (2)在舌间充质中，Wnt1-Cre标记的NC衍生细胞与味乳头和味蕾密切相关。 Wnt1-Cre 驱动的骨形态发生蛋白 (BMP) I 型受体 Alk2 和 Alk3 的条件性遗传修饰以水平、阶段和受体特异性方式显着改变舌头、味乳头和味蕾的形成和维持。这表明舌头间充质中的 BMP 信号通过不同的受体与上皮相互作用，在舌头、味乳头和味蕾的发育中发挥不同的作用。拟议的研究将利用现代技术（Cre介导的基因修饰）以及体内和体外研究的结合来解决有关味觉乳头器官形成的基本问题。我们的目标是：（目标 1）展示 NC 细胞迁移到舌原基上皮的最佳阶段 (1a) 和初级颅区域（中脑或后脑）(1b)；这些细胞何时以及有多少在舌上皮中分化以获得特定的细胞表型 (1c)；哪些类型和比例的味蕾细胞源自 NC (1d)；（目标 2）描述舌间充质 NC 衍生细胞中的 BMP 信号如何通过不同的 I 型受体（ALK2 和 ALK3）与上皮细胞相互作用，以促进舌头、味觉乳头和味蕾的发育和维持，并进行基因修饰(2a) 通过 Wnt1-Cre 驱动的 Alk2 或 Alk3 条件性敲除来下调 BMP 信号传导活性； (2b) 通过 Wnt1-Cre 驱动每个受体的条件组成性激活来上调 BMP 信号传导。总体而言，拟议的味觉乳头和味蕾细胞起源、分化和间质相互作用研究将有助于理解味觉器官的发育，并将为神经嵴对味觉乳头和味觉的贡献领域带来新的信息和新的视角。芽细胞。