Development of the renin-expressing cell

描述(由申请人提供)： 肾素合成细胞在调节血压、体液和电解质的动态平衡方面起着至关重要的作用。这些细胞被认为是终末分化的，因为它们合成一种激素(肾素)，数量很少，并且局限于成年哺乳动物肾脏的肾小球旁定位。然而，最近我们发现肾素细胞是多种肾脏和肾外细胞类型的前体。虽然肾素细胞来自中胚层已被接受，但我们的初步工作表明，肾素表达细胞的一部分或全部可能来自外胚层。我们进一步假设，肾素是外胚层前体分化为其衍生组织(即皮肤、脉络丛、交感神经节、肾上腺髓质和头软骨)所必需的。为了确定肾素表达的细胞是来自神经外胚层还是神经脊细胞，我们将使用可用的小鼠模型来标记来自神经外胚层、神经嵴和肾素细胞谱系的细胞。为了确定神经外胚层/神经脊/表皮前体中肾素基因的缺失是否会导致其衍生组织的发育缺陷，我们将产生一只肾素漂浮的小鼠，并将其与神经外胚层(Nestin-cre)、神经脊细胞(wnt1-cre)和表皮(k14-cre)的前体中表达ere重组酶的小鼠杂交。 拟议的研究将产生关于肾素细胞规格和神经/外胚层发育的基本新知识。此外，产生肾素漂浮的小鼠将是一个有价值的工具，以解决长期存在的关于局部产生的肾素与循环中的肾素的作用的争议。这项工作有可能为了解、预防和治疗高血压、出生缺陷和肾脏疾病开辟新的途径。

DESCRIPTION (provided by applicant): Renin-synthesizing cells are known to be crucial in the regulation of blood pressure and fluid and electrolyte homeostasis. These cells have been considered as terminally differentiated because they synthesize a hormone (renin), are few in numbers, and are restricted to a juxtaglomerular localization in the adult mammalian kidney. Recently, however, we showed that renin cells are precursors for multiple renal and extrarenal cell types. Although it has been accepted that renin cells derive from the mesoderm, our preliminary work indicates that either a subset or all of the renin-expressing cells may derive from ectoderm. We further hypothesize that renin is necessary for the differentiation of ectodermal precursors into their derivative tissues (i.e. skin, choroid plexus, sympathetic ganglia, adrenal medulla and head cartilage). To define whether renin-expressing cells derive from neuroectodermal or neural crest cells we will use available mouse models that mark cells derived from the neuroectoderm, the neural crest and the renin cell lineage. To determine whether deletion of the renin gene in neuroectodermal/neural crest/ epidermal precursors results in defective development of their derivative tissues, we will generate a renin-floxed mouse and will cross it with mice expressing ere recombinase in precursors of neuroectoderm (nestin-cre), neural crest cells (wnt1-cre) and epidermis (K14-cre). The proposed studies should generate fundamental new knowledge on renin cell specification and neural/ectodermal development. Furthermore, the generation of a renin-floxed mouse will be a valuable tool to solve the long standing controversy regarding the role of locally generated renin versus circulating renin. This work has the potential to open new avenues for the understanding, prevention and treatment of hypertension, birth defects and kidney diseases.