Boucherat Olivier, Guillou François, Aubin Josée, Jeannotte Lucie
Centre de recherche en cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, 9, rue McMahon, Québec G1R 2J6, Canada.
Med Sci (Paris). 2009 Jan;25(1):77-82. doi: 10.1051/medsci/200925177.
The Hox gene family occupies a central position in the control of body patterning by regulating the transcription of downstream effectors that, in turn, direct the morphogenetic events leading to the complex body forms along the axes. Analysis of Hox mutant mouse lines has revealed a panoply of phenotypes indicative of the broad range of Hox genes action throughout embryonic and postnatal life. Although Hox genes have been the subject of extensive research in the last two decades, the comprehension of the mechanisms involved in their regulation and function still remains elusive. Here, we present an overview of our current knowledge about one Hox gene family member, Hoxa5. The phenotypic survey of Hoxa5 mutant mice has unveiled the crucial role of this gene in regulating morphogenesis and specifying regional identity along the embryo. A majority of Hoxa5 mutant pups die at birth from defective respiratory tract. Surviving mutants present deficient alveolar septation revealing the importance of Hoxa5 during formation and maturation of the lung. Hoxa5 also participates in the morphogenesis of the digestive tract as well as that of the thyroid and mammary glands. Hoxa5 expression is restricted to the mesenchyme, and its action appears to be mediated through the control of mesenchymal-epithelial interactions during organogenesis. The implication of Hoxa5 in tumorigenesis has also been documented. In breast cancer, Hoxa5 down-regulation may impact on p53 gene expression, contributing to the oncogenic process. In contrast, the loss of Hoxa5 function limits leukaemia associated with specific chromosomal translocations. Thus, inappropriate Hoxa5 gene expression may disrupt normal growth and differentiation programs causing neoplasia. Hox gene function is intimately linked to its correct expression. Regulation of Hoxa5 expression requires multiple cis-acting regions, some encompassing coding sequences from neighboring genes. Moreover, it is complicated by the presence of several transcription units. Together these data enlighten the importance of Hox cluster organization in Hoxa5 function.
Hox基因家族在身体模式控制中占据核心地位，它通过调节下游效应器的转录来发挥作用，而这些效应器反过来又指导导致沿轴形成复杂身体形态的形态发生事件。对Hox突变小鼠品系的分析揭示了一系列表型，表明Hox基因在整个胚胎期和出生后生活中具有广泛的作用。尽管在过去二十年中Hox基因一直是广泛研究的对象，但对其调控和功能所涉及机制的理解仍然难以捉摸。在此，我们概述了我们目前对一个Hox基因家族成员Hoxa5的了解。对Hoxa5突变小鼠的表型调查揭示了该基因在调节形态发生和确定胚胎沿轴的区域特征方面的关键作用。大多数Hoxa5突变幼崽出生时因呼吸道缺陷而死亡。存活的突变体表现出肺泡间隔不足，揭示了Hoxa5在肺形成和成熟过程中的重要性。Hoxa5还参与消化道以及甲状腺和乳腺的形态发生。Hoxa5的表达仅限于间充质，其作用似乎是通过在器官发生过程中控制间充质-上皮相互作用来介导的。Hoxa5在肿瘤发生中的作用也有文献记载。在乳腺癌中，Hoxa5的下调可能影响p53基因的表达，促进致癌过程。相反，Hoxa5功能的丧失会限制与特定染色体易位相关的白血病。因此，Hoxa5基因的异常表达可能会破坏正常的生长和分化程序，导致肿瘤形成。Hox基因的功能与其正确表达密切相关。Hoxa5表达的调控需要多个顺式作用区域，其中一些区域包含来自相邻基因的编码序列。此外，由于存在几个转录单元，情况变得复杂。这些数据共同揭示了Hox簇组织在Hoxa5功能中的重要性。
