DOWNLESS GENE AND ITS ROLE IN INDUCTIVE SIGNALING

描述：(改编自申请人的摘要)-归纳 相邻组织之间的相互作用对于规范 正常胚胎发育过程中的发育决策。有三只老鼠 突变体，羽绒，猫和皱纹，都在 毛囊、汗腺和眉毛腺的外胚层诱导。 嫁接实验表明，这些基因在外胚层中表达。 外胚层需要它们才能对 来自相邻间充质细胞的诱导信号。这项建议是有重点的 在这些基因中的一个上，无绒毛。患有常染色体遗传性疾病的人 无汗性外胚层发育不良(EDA)表现出本质上是 与无绒毛表型相同。几年前，校长 研究人员发现了无绒基因的插入突变；因为 然后，他进行了这种基因的定位克隆，并发现了一种 小的200kb的YAC含有名为D9的基因。YAC现在已经被使用了 以治愈转基因小鼠的无绒毛突变。在本提案中， 本论文的主要目的有四个：1)筛选和评价候选的无羽绒基因 2)隐性Dlj和显性负Dlslk的鉴定 突变和寻找人类EDA同源基因的突变 病人；3)确定和操纵dl的表达模式。 在胚胎发育期间，以及4)识别与之相互作用的蛋白质 无绒毛蛋白质，并确定这些是否由猫编码 和/或皱缩的基因。有人建议，对模式的操纵 在小鼠中的无下调基因表达将有助于确定诱导能力 和细胞命运指标，并可用来评估 产后汗腺诱导有助于预防人类体温过高 患有EDA的患者。

DESCRIPTION: (Adapted from the applicant's abstract) - Inductive interactions between adjacent tissues are important for specification of developmental decisions during normal embryogenesis. There are three mouse mutants, downless, Tabby, and crinkled, that all show identical defects in ectodermal induction of hair follicles, sweat glands, and Meibomian glands. Grafting experiments indicate that these genes are expressed in the ectoderm and that they are required for the ectoderm to be competent to respond to inductive signals from adjacent mesenchymal cells. This proposal is focused on one of these genes, downless. People with the genetic disorder autosomal anhidrotic ectodermal dysplasia (EDA) exhibit defects that are essentially identical to the downless phenotype. A number of years ago, the principal investigator identified insertional mutations in the downless gene; since then he has pursued the positional cloning of this gene and has identified a small 200kb YAC that contains the gene called D9. The YAC has now been used to cure the downless mutation in transgenic mice. In the present proposal, four aims are outlined: 1) To identify and evaluate candidate downless cDNA clones; 2) to identify the recessive dlJ and dominant negative Dlslk mutations and to look for mutations in the homologous gene in human EDA patients; 3) to determine and manipulate the patterns of dl expression during embryonic development, and 4) to identify proteins that interact with the downless protein and to determine whether these are encoded by the Tabby and/or crinkled genes. It is proposed that manipulations of the pattern of downless gene expression in mice will help to define inductive competence and cell fate specification and can be used to assess the feasibility of post-natal sweat gland induction to help prevent hyperthermia in human patients with EDA.