Ueno Naoto, Greene Nicholas D E
Department of Developmental Biology, National Institute for Basic Biology, and SOKENDAI, Okazaki, Japan.
Birth Defects Res C Embryo Today. 2003 Nov;69(4):318-24. doi: 10.1002/bdrc.10029.
Closure of the neural tube is essential for normal development of the brain and spinal cord. Failure of closure results in neural tube defects (NTDs), common and clinically severe congenital malformations whose molecular mechanisms remain poorly understood. On the other hand, it is increasingly well established that common molecular mechanisms are employed to regulate morphogenesis of multicellular organisms. For example, signaling triggered by polypeptide growth factors is highly conserved among species and utilized in multiple developmental processes. Recent studies have revealed that the Drosophila planar cell polarity (PCP) pathway, which directs position and direction of wing hairs on the surface of the fly wing, is well conserved, and orthologs of several genes encoding components of the pathway are also found in vertebrates. Interestingly, in vertebrates, this signaling pathway appears to be co-opted to regulate "convergent extension" cell movements during gastrulation. Disruption of vertebrate PCP genes in Xenopus laevis or zebrafish causes severe gastrulation defects or the shortening of the trunk, as well as mediolateral expansion of somites. In Xenopus, in which the neural tube closes by elevation and fusion of neural folds, inhibition of convergent extension can also prevent neural tube closure causing a "spina bifida-like" appearance. Furthermore, several of the genes involved in the PCP pathway have recently been shown to be required for neural tube closure in the mouse, since mutation of these genes causes NTDs. Therefore, understanding the mechanisms underlying the establishment of cell polarity in Drosophila may provide important clues to the molecular basis of NTDs.
神经管的闭合对于脑和脊髓的正常发育至关重要。闭合失败会导致神经管缺陷(NTDs),这是常见且临床严重的先天性畸形,其分子机制仍知之甚少。另一方面,越来越明确的是,多细胞生物形态发生的调控采用了共同的分子机制。例如,多肽生长因子触发的信号在物种间高度保守,并用于多个发育过程。最近的研究表明,果蝇平面细胞极性(PCP)通路可指导果蝇翅膀表面翅毛的位置和方向,该通路高度保守,在脊椎动物中也发现了编码该通路成分的几个基因的直系同源物。有趣的是,在脊椎动物中,这条信号通路似乎被用于调节原肠胚形成过程中的“汇聚延伸”细胞运动。非洲爪蟾或斑马鱼中脊椎动物PCP基因的破坏会导致严重的原肠胚形成缺陷或躯干缩短,以及体节的中外侧扩展。在神经管通过神经褶的抬高和融合而闭合的非洲爪蟾中,抑制汇聚延伸也会阻止神经管闭合,导致“脊柱裂样”外观。此外,最近有研究表明,PCP通路中的几个基因在小鼠神经管闭合中是必需的,因为这些基因的突变会导致神经管缺陷。因此,了解果蝇中细胞极性建立的机制可能为神经管缺陷的分子基础提供重要线索。