TARGETED DISRUPTIONS OF THE MURINE HOXA-4 AND HOXA-6 GENES RESULT IN HOMEOTIC TRANSFORMATIONS OF COMPONENTS OF THE VERTEBRAL COLUMN
TARGETED DISRUPTIONS OF THE MURINE HOXA-4 AND HOXA-6 GENES RESULT IN HOMEOTIC TRANSFORMATIONS OF COMPONENTS OF THE VERTEBRAL COLUMN
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DOI：
10.1016/0925-4773(94)90073-6
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发表时间：
1994-06-01
影响因子：
2.6
通讯作者：
CAPECCHI, MR
中科院分区：
文献类型：
--
作者：
KOSTIC, D;CAPECCHI, MR
越来越清楚的是，Hox基因，编码转录因子的同源结构域家族，是建立哺乳动物胚胎的身体计划的关键球员。它们已经涉及到中枢神经系统的形成，神经嵴，脊柱和四肢衍生的组织。为了研究hoxa-4和hoxa-6在发育过程中的作用，产生了这些基因中具有靶向破坏的小鼠。每一个都显示了颈椎的同源异型转化，其位置接近这些基因在前椎骨中表达的前边界。在正常表达这些基因的其他组织中没有观察到缺陷。Hoxa-4（-）/Hoxa-4（-）小鼠通过获得通常与第二颈椎相关的特征，显示出100%的前向变形，即第三颈椎的背侧。hoxa-6突变纯合子小鼠表现出第七颈椎向第一胸椎的后部转化，即使在同一动物的相对两侧也是不完全的转移。此外，hoxa-4（-）/hoxa-4（-）和hoxa-6（-）/hoxa-6（-）小鼠表现出表达能力的变化。这些数据表明，替代遗传途径可以部分，有时完全取代这两个基因的功能。这两个旁系同源Hox家族的其他成员是提供替代的良好候选者。由于旁系同源基因位于不同的染色体上，因此有可能通过将小鼠与适当的个体中断杂交来检查这些基因之间的冗余程度。对双重、三重甚至四重突变体的分析应该确定这些Hox基因相互作用的方式，以便在发育中的小鼠胚胎的限制区域中指定大量组织。
It is becoming clear that Hox genes, which encode transcription factors of the Antennapedia homeodomain family, are key players in establishing the body plan of mammalian embryos. They have already been implicated in the formation of the central nervous system, tissues derived from neural crest, the vertebral column and the limbs. In order to examine the roles of hoxa-4 and hoxa-6 during development, mice with targeted disruptions in these genes were generated. Each shows homeotic transformation of cervical vertebrae, at positions that approximate the anterior borders of expression of these genes in the prevertebrae. Defects were not observed in other tissues that normally express these genes. Hoxa-4(-)/hoxa-4(-) mice show, with 100% penetrance, anterior transformations of the dorsal aspects of the third cervical vertebra by acquiring features normally associated with the second cervical vertebra. Mice homozygous for the hoxa-6 mutation show, with incomplete penetrance, even on opposite sides of the same animal, posterior transformations of the seventh cervical vertebra to the first thoracic vertebra. In addition, both hoxa-4(-)/hoxa-4(-) and hoxa-6(-)/hoxa-6(-) mice show variability in expressivity. These data indicate that alternative genetic pathways can partially, and at times completely, substitute for the function of these two genes. Other members of these two paralogous Hox families are good candidates for providing the substitutions. As paralogous genes lie on different chromosomes, it is possible to examine the degree of redundancy among these genes by intercrossing mice with the appropriate individual disruptions. The analysis of double, triple and even quadruple mutants should determine the ways in which these Hox genes interact in order to specify the multitude of tissues in a restricted region of the developing mouse embryo.