Sucov H M, Izpisúa-Belmonte J C, Gañan Y, Evans R M
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Development. 1995 Dec;121(12):3997-4003. doi: 10.1242/dev.121.12.3997.
Embryonic exposure to the vitamin A metabolite retinoic acid (RA) causes malformations in numerous developing tissues, including the limbs, which serves as a model system of retinoic acid action. RA treatment of wild-type mouse embryos results in digit truncations and long bone reductions. These effects are mediated by products of the retinoic acid and retinoid X receptor genes (RARs and RXRs), members of the nuclear receptor family of ligand-dependent transcription factors. Mouse embryos homozygous for a mutation in the RXR alpha gene appear normal in limb development, although such embryos are phenotypically affected in other tissues. We now describe resistance to limb malformations normally induced by teratogenic RA exposure in the RXR alpha-/- background. RA treatments that cause limb defects in 100% of wild-type embryos fail to elicit malformations in RXR alpha homozygotes, implicating RXR alpha as a component in the teratogenic process in the limbs. Heterozygous embryos are intermediate in sensitivity to RA, suggesting the importance of RXR alpha gene dosage in limb teratogenesis. Expression of the RA-inducible gene RAR beta 2 was equivalent between wild-type and homozygous embryos after RA treatment. RA treatment also did not distinguish between wild-type and RXR alpha -/- embryos in the spatial expression of sonic hedgehog (Shh) and hoxd-12, two other genes implicated in limb development. However, the quantitative level of hoxd-12 expression was elevated in RXR alpha -/- embryos. These observations indicate that transcriptional processes which are inappropriately regulated in the mouse limb by exogenous RA require RXR alpha for their execution, and that specific teratogenic processes, as well as specific normal developmental processes under vitamin A control, occur through individual members of the RXR and RAR families.
胚胎期暴露于维生素A代谢产物视黄酸（RA）会导致许多发育中的组织出现畸形，包括四肢，四肢可作为视黄酸作用的模型系统。用RA处理野生型小鼠胚胎会导致指骨截断和长骨变短。这些效应是由视黄酸和视黄醇X受体基因（RARs和RXRs）的产物介导的，它们是配体依赖性转录因子核受体家族的成员。RXRα基因发生突变的纯合子小鼠胚胎在四肢发育上看起来正常，尽管这些胚胎在其他组织中表现出表型异常。我们现在描述在RXRα基因敲除背景下对致畸性RA暴露通常诱导的四肢畸形具有抗性。在100%的野生型胚胎中导致四肢缺陷的RA处理未能在RXRα纯合子中引发畸形，这表明RXRα是四肢致畸过程中的一个组成部分。杂合子胚胎对RA的敏感性处于中间水平，这表明RXRα基因剂量在四肢致畸作用中很重要。RA处理后，野生型和纯合子胚胎中RA诱导基因RARβ2的表达相当。RA处理在另两个与四肢发育有关的基因——音猬因子（Shh）和hoxd - 12的空间表达上也未区分野生型和RXRα基因敲除胚胎。然而，RXRα基因敲除胚胎中hoxd - 12表达的定量水平有所升高。这些观察结果表明，外源性RA在小鼠四肢中不适当调节的转录过程需要RXRα来执行，并且特定的致畸过程以及维生素A控制下的特定正常发育过程是通过RXR和RAR家族的各个成员发生的。
