Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism.
Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism.
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DOI：
10.1016/j.ydbio.2009.10.029
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发表时间：
2010-02-01
影响因子：
2.7
通讯作者：
Moens, C. B.
中科院分区：
文献类型：
--
作者：
Feng, L.;Hernandez, R. E.;Waxman, J. S.;Yelon, D.;Moens, C. B.
关键词：
视黄酸（RA）是一种重要的发育信号分子，负责多种脊椎动物组织的图案化。RA也是一种强效致畸剂，导致人类多器官出生缺陷。因此，在发育中的胚胎中必须严格控制内源性RA水平。我们使用微阵列的方法来确定基因的功能作为负反馈调节剂的视黄酸信号。我们筛选了在早期体节阶段胚胎中表达的基因，这些基因对RA与RA拮抗剂治疗的反应相反，并通过RNA原位杂交对其进行了验证。专注于已知参与RA代谢的基因，我们确定dhrs 3a，它编码的短链脱氢酶/还原酶蛋白家族的成员，是RA依赖和强烈RA诱导。已知Dhrs 3a催化RA前体全反式视黄醇还原为维生素A，然而发育功能尚未得到证实。使用吗啉敲低和mRNA过表达，我们证明Dhrs 3a是必需的，以限制RA水平在胚胎中，主要是在中枢神经系统。因此，Dhrs 3a是RA诱导的RA生物合成的反馈抑制剂。我们的结论是，视黄醛的可用性是一个重要的水平，RA的生物合成调节脊椎动物胚胎。
Retinoic acid (RA) is an important developmental signaling molecule responsible for the patterning of multiple vertebrate tissues. RA is also a potent teratogen, causing multi-organ birth defects in humans. Endogenous RA levels must therefore be tightly controlled in the developing embryo. We used a microarray approach to identify genes that function as negative feedback regulators of retinoic acid signaling. We screened for genes expressed in early somite-stage embryos that respond oppositely to treatment with RA versus RA antagonists, and validated them by RNA in situ hybridization. Focusing on genes known to be involved in RA metabolism, we determined that dhrs3a, which encodes a member of the short-chain dehydrogenase/reductase protein family, is both RA dependent and strongly RA inducible. Dhrs3a is known to catalyze the reduction of the RA precursor all-trans retinaldehyde to vitamin A, however a developmental function has not been demonstrated. Using morpholino knock down and mRNA over-expression, we demonstrate that Dhrs3a is required to limit RA levels in the embryo, primarily within the central nervous system. Dhrs3a is thus an RA-induced feedback inhibitor of RA biosynthesis. We conclude that retinaldehyde availability is an important level at which RA biosynthesis is regulated in vertebrate embryos.
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影响因子：
64.5
作者：
Duester G
通讯作者：
Duester G
影响因子：
10.5
作者：
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通讯作者：
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影响因子：
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作者：
BOUILLET, P;OULADABDELGHANI, M;CHAMBON, P
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RIP140在诱导多能人类胚胎癌细胞的肿瘤细胞分化过程中对视黄酸靶基因的选择性抑制。
影响因子：
37.3
作者：
Heim, Kelly C;White, Kristina A;Deng, Dexin;Tomlinson, Craig R;Moore, Jason H;Freemantle, Sarah J;Spinella, Michael J
通讯作者：
Spinella, Michael J
影响因子：
2.7
作者：
Jülich, D;Lim, CH;Holley, SA
通讯作者：
Holley, SA