Gur Michal, Bendelac-Kapon Liat, Shabtai Yehuda, Pillemer Graciela, Fainsod Abraham
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Front Cell Dev Biol. 2022 Mar 14;10:844619. doi: 10.3389/fcell.2022.844619. eCollection 2022.
Retinoic acid (RA) is a central signaling molecule regulating multiple developmental decisions during embryogenesis. Excess RA induces head malformations, primarily by expansion of posterior brain structures at the expense of anterior head regions, i.e., hindbrain expansion. Despite this extensively studied RA teratogenic effect, a number of syndromes exhibiting microcephaly, such as DiGeorge, Vitamin A Deficiency, Fetal Alcohol Syndrome, and others, have been attributed to reduced RA signaling. This causative link suggests a requirement for RA signaling during normal head development in all these syndromes. To characterize this novel RA function, we studied the involvement of RA in the early events leading to head formation in embryos. This effect was mapped to the earliest RA biosynthesis in the embryo within the gastrula Spemann-Mangold organizer. Head malformations were observed when reduced RA signaling was induced in the endogenous Spemann-Mangold organizer and in the ectopic organizer of twinned embryos. Two embryonic retinaldehyde dehydrogenases, ALDH1A2 (RALDH2) and ALDH1A3 (RALDH3) are initially expressed in the organizer and subsequently mark the trunk and the migrating leading edge mesendoderm, respectively. Gene-specific knockdowns and CRISPR/Cas9 targeting show that RALDH3 is a key enzyme involved in RA production required for head formation. These observations indicate that in addition to the teratogenic effect of excess RA on head development, RA signaling also has a positive and required regulatory role in the early formation of the head during gastrula stages. These results identify a novel RA activity that concurs with its proposed reduction in syndromes exhibiting microcephaly.
视黄酸（RA）是一种核心信号分子，在胚胎发育过程中调节多个发育决策。过量的RA会诱导头部畸形，主要是通过扩展后脑结构，以牺牲前脑区域为代价，即后脑扩张。尽管对RA的致畸作用进行了广泛研究，但一些表现为小头畸形的综合征，如迪格奥尔格综合征、维生素A缺乏症、胎儿酒精综合征等，都被归因于RA信号传导减少。这种因果关系表明，在所有这些综合征的正常头部发育过程中，RA信号传导是必需的。为了表征这种新的RA功能，我们研究了RA在胚胎头部形成早期事件中的作用。这种作用被定位到原肠胚斯佩曼-曼戈尔德组织者内胚胎最早的RA生物合成过程。当在内源性斯佩曼-曼戈尔德组织者和双胎胚胎的异位组织者中诱导RA信号传导减少时，观察到了头部畸形。两种胚胎视黄醛脱氢酶，醛脱氢酶1A2（RALDH2）和醛脱氢酶1A3（RALDH3）最初在组织者中表达，随后分别标记躯干和迁移的前缘中胚层。基因特异性敲低和CRISPR/Cas9靶向显示，RALDH3是头部形成所需的RA产生过程中的关键酶。这些观察结果表明，除了过量RA对头部发育的致畸作用外，RA信号传导在原肠胚阶段头部的早期形成中也具有积极且必需的调节作用。这些结果确定了一种新的RA活性，这与其在表现为小头畸形的综合征中所提出的减少情况相一致。
