Department of Medical Neurobiology, Institute of Medical Research Israel-Canada (IMRIC) and the Edmond and Lily Safra Center for Brain Sciences (ELSC), Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel.
Elife. 2022 Apr 8;11:e72723. doi: 10.7554/eLife.72723.
Production and emigration of neural crest cells is a transient process followed by the emergence of the definitive roof plate. The mechanisms regulating the end of neural crest ontogeny are poorly understood. Whereas early crest development is stimulated by mesoderm-derived retinoic acid, we report that the end of the neural crest period is regulated by retinoic acid synthesized in the dorsal neural tube. Inhibition of retinoic acid signaling in the neural tube prevents the normal upregulation of BMP inhibitors in the nascent roof plate and prolongs the period of BMP responsiveness which otherwise ceases close to roof plate establishment. Consequently, neural crest production and emigration are extended well into the roof plate stage. In turn, extending the activity of neural crest-specific genes inhibits the onset of retinoic acid synthesis in roof plate suggesting a mutual repressive interaction between neural crest and roof plate traits. Although several roof plate-specific genes are normally expressed in the absence of retinoic acid signaling, roof plate and crest markers are co-expressed in single cells and this domain also contains dorsal interneurons. Hence, the cellular and molecular architecture of the roof plate is compromised. Collectively, our results demonstrate that neural tube-derived retinoic acid, via inhibition of BMP signaling, is an essential factor responsible for the end of neural crest generation and the proper segregation of dorsal neural lineages.
神经嵴细胞的产生和迁移是一个短暂的过程，随后出现明确的顶板。调节神经嵴发生结束的机制还知之甚少。虽然早期嵴的发育受到中胚层衍生的视黄酸的刺激，但我们报告说，神经嵴时期的结束受背部神经管中合成的视黄酸调节。在神经管中抑制视黄酸信号会阻止正常的 BMP 抑制剂在上皮嵴中的上调，并延长 BMP 反应性的时间，否则在接近上皮嵴建立时会停止。因此，神经嵴的产生和迁移被延长到了上皮嵴阶段。反过来，延长神经嵴特异性基因的活性会抑制上皮嵴中视黄酸合成的开始，这表明神经嵴和上皮嵴特征之间存在相互抑制的相互作用。尽管在没有视黄酸信号的情况下，几个上皮嵴特异性基因通常会表达，但上皮嵴和嵴标记物在单个细胞中共同表达，并且该区域还包含背侧中间神经元。因此，上皮嵴的细胞和分子结构受到损害。总之，我们的结果表明，神经管衍生的视黄酸通过抑制 BMP 信号，是负责神经嵴发生结束和背侧神经谱系正确分离的必需因素。
