FUNCTIONAL ANALYSIS OF DEFORMED CLASS HOX GENES

变形HOX类基因的功能分析

基本信息

批准号：
2403372
负责人：
Richard R Behringer
金额：
$ 14.61万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 1999-04-30
项目状态：
已结题

项目摘要

There are over 35 mouse homeobox-containing genes known as Hox. The Hox genes are divided into four multigene dusters (Hox-A, -B, -C, & -D), which reside on four different chromosomes. These genes are expressed in restricted patterns during embryogenesis. The function of Hox genes during mammalian development was first studied by overexpressing the Hoxa-4 gene in transgenic mice (Wolgemuth et al., 1989). That study demonstrated for the first time that the expression of a mammalian homeobox-containing gene could alter development. Since then, studies using gain of function and loss of function transgenic mice have suggested that the Hox genes constitute a complex genetic network for patterning the mouse embryo. In this application, experiments are proposed to study the individual and combined roles of a specific class of Hox genes during mouse development. This class of mouse Hox genes is known as the Deformed class or Group 4, which includes the four Hox genes Hoxa-4, b-4, c-4, and d-4. These Hox genes possess a homeodomain most similar to Drosophila Deformed and constitute a paralogous group of genes between the clusters. Gene targeting experiments have been initiated using mouse embryonic stem (ES) cells to generate Hoxa-4, c-4, and d-4 mutations in the germ line of mice to study their required functions during mammalian development. Germ line chimeras derived from Hoxa-4 mutant ES cells have already been generated. In addition to the individual Hox phenotypes, mice carrying these three Hox mutations and the recently reported Hoxb-4 mutation (Ramirez-Solis et al., 1993) will be interbred to produce mice deficient for two or more of these genes. The production of mouse strains that possess the four Deformed-class Hox gene mutations will provide a powerful resource for studying the function of Hox genes. These focused studies should provide important information about the roles of a specific class of Hox genes during mouse development. The information gained in this model system should be useful in understanding normal and abnormal human development.

有超过35个含有同源的小鼠同源基因称为HOX。霍克斯基因分为四个多基因杜斯（Hox -a，-b，-c，＆-d），它们分为驻留在四个不同的染色体上。这些基因在胚胎发生过程中的限制模式。 HOX基因的功能首先通过表达Hoxa-4基因来研究哺乳动物的发育在转基因小鼠中（Wolgemuth等，1989）。这项研究证明了第一次表达含哺乳动物同源的基因可以改变发展。从那以后，使用功能获得的研究和功能转基因小鼠的功能损失表明HOX基因构成一个复杂的遗传网络，用于对小鼠胚胎进行图案。在该应用，提出了实验来研究个体和在小鼠发育过程中，特定类基因的特定类别的作用结合在一起。这类小鼠HOX基因被称为变形类或组4，其中包括四个HOX基因HOXA-4，B-4，C-4和D-4。这些hox 基因具有与果蝇变形最相似的同源构域，构成簇之间的一组基因。基因使用小鼠胚胎茎（ES）启动了靶向实验细胞在小鼠的生殖线中生成HOXA-4，C-4和D-4突变在哺乳动物发育过程中研究其所需功能。细菌系源自HOXA-4突变ES细胞的嵌合体已经产生。除了单个HOX表型，携带这三只的小鼠 HOX突变和最近报道的HOXB-4突变（Ramirez-Solis et Al。，1993）将被杂交以产生缺乏两个或多个的小鼠这些基因。拥有四个的小鼠菌株的产生变形级HOX基因突变将为研究HOX基因的功能。这些重点研究应提供有关特定类别基因角色的重要信息在小鼠发育过程中。在此模型系统中获得的信息应该有助于理解正常和异常的人类发展。