Wolgemuth D J, Behringer R R, Mostoller M P, Brinster R L, Palmiter R D
Department of Genetics and Development, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
Nature. 1989 Feb 2;337(6206):464-7. doi: 10.1038/337464a0.
The mouse homoeobox-containing genes exhibit temporally and spatially specific patterns of expression in embryonic and adult tissues and are thought to be important in regulation of development and cellular differentiation, perhaps by mechanisms analogous to homoeotic genes in Drosophila melanogaster. There has been no direct demonstration that expression of these mammalian genes can affect developmental processes, however. Hox-1.4, like other mouse homoeobox-containing genes, has been shown to be expressed in specific regions of the mid-gestation embryo, but is unique in that its highest level of expression in the adult animal is restricted to developing male germ cells. We have introduced a construct carrying the mouse Hox-1.4 gene into the germ line of mice to begin to identify the cis-acting elements required for proper expression and to assess the consequences of increasing Hox-1.4 gene expression. The construct was designed to produce normal Hox-1.4 protein from transcripts that are distinguishable from the products of the endogenous gene. The integrated transgene seemed to exhibit the appropriate tissue specificity of expression, but transcript levels were elevated in certain tissues, particularly the embryonic gut. This overexpression correlated with changes in the normal developmental program of the gut, resulting in an inherited abnormal phenotype known as megacolon.
含小鼠同源异型框的基因在胚胎组织和成年组织中呈现出时间和空间上的特异性表达模式，并且被认为在发育调控和细胞分化中发挥重要作用，其作用机制可能类似于果蝇中的同源异型基因。然而，目前尚无直接证据表明这些哺乳动物基因的表达能够影响发育过程。与其他含小鼠同源异型框的基因一样，Hox-1.4已被证明在妊娠中期胚胎的特定区域表达，但其独特之处在于，在成年动物中，其最高表达水平仅限于发育中的雄性生殖细胞。我们已将携带小鼠Hox-1.4基因的构建体导入小鼠生殖系，以开始鉴定正确表达所需的顺式作用元件，并评估增加Hox-1.4基因表达的后果。该构建体旨在从与内源基因产物可区分的转录本中产生正常的Hox-1.4蛋白。整合的转基因似乎表现出适当的组织特异性表达，但某些组织中的转录本水平升高，尤其是胚胎肠道。这种过表达与肠道正常发育程序的变化相关，导致一种遗传性异常表型，即巨结肠。
