Function of retinoic acid receptors during embryonic development.
Function of retinoic acid receptors during embryonic development.
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DOI：
10.1621/nrs.07002
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Chambon P
中科院分区：
文献类型：
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作者：
Mark M;Ghyselinck NB;Chambon P
类维生素A是维生素A的活性代谢物，调节参与脊椎动物形态发生、生长、细胞分化和体内平衡的复杂基因网络。使用无细胞系统或转染细胞进行的体外研究表明，类维生素A作用是通过RAR和RXR核受体之间的异二聚体介导的。然而，体外研究表明了可能的情况，但不一定表明体内实际发生的情况，因为它们是在非生理条件下进行的。因此，动物的遗传方法已被用来确定类维生素A受体的生理功能。胚胎干细胞中的同源重组已被用于在小鼠中产生 RAR 和 RXR 编码基因的种系无效突变。正如本文所述，此类种系突变的产生与阻断 RA 信号通路的药理学方法相结合，提供了遗传证据，表明 RAR/RXR 异二聚体确实是在产前发育过程中转导 RA 信号的功能单位。然而，由于（i）通过多个 RAR 和 RXR 转导的“激素”信号传导的复杂性，（ii）属于特定家族的受体同种型内的功能冗余（可能是由突变人为产生的），以及（iii）某些种系无效突变在子宫内或产后早期的致死性，这些遗传学研究未能揭示 RAR 和 RXR 的所有生理功能，特别是在成人中。在给定的细胞类型/组织中以及在出生后的选定时间产生的时空控制的体细胞突变将需要揭示小鼠一生中 RAR 和 RXR 的所有功能。
Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation and homeostasis. Studies performed in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the RAR and RXR nuclear receptors. However, in vitro studies indicate what is possible, but not necessarily what is actually occurring in vivo, because they are performed under non-physiological conditions. Therefore, genetic approaches in the animal have been be used to determine the physiological functions of retinoid receptors. Homologous recombination in embryonic stem cells has been used to generate germline null mutations of the RAR- and RXR-coding genes in the mouse. As reviewed here, the generation of such germline mutations, combined with pharmacological approaches to block the RA signalling pathway, has provided genetic evidence that RAR/RXR heterodimers are indeed the functional units transducing the RA signal during prenatal development. However, due to (i) the complexity in “hormonal” signalling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given family, and (iii) in utero or early postnatal lethality of certain germline null mutations, these genetic studies have failed to reveal all the physiological functions of RARs and RXRs, notably in adults. Spatio-temporally-controlled somatic mutations generated in given cell types/tissues and at chosen times during postnatal life, will be required to reveal all the functions of RAR and RXR throughout the lifetime of the mouse.