Brennan A, Dean C H, Zhang A L, Cass D T, Mirsky R, Jessen K R
Department of Anatomy and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
Dev Biol. 2000 Nov 15;227(2):545-57. doi: 10.1006/dbio.2000.9887.
Schwann cell precursors, derivatives of the neural crest, generate Schwann cells in a process that is tightly timed, well characterized, and directly controlled by axonal signals, in particular beta-neuregulins. Here we provide evidence that endothelins (ETs) are also important for survival and lineage progression in this system. We show that ETs promote rat Schwann cell precursor survival in vitro without stimulation of DNA synthesis. Using ET receptor agonists and antagonists, we demonstrate that this action of ET is mediated by the ET(B) receptor. RT-PCR reveals the presence of ET and ET receptor mRNA in the developing rat PNS. We showed previously that in vitro beta-neuregulins promote the generation of Schwann cells from precursors on schedule and that this process can be accelerated by fibroblast growth factor 2. Here we show that although ETs promote long-term precursor survival the transition of precursors to Schwann cells is delayed. Moreover, ETs block the maturation effects of beta-neuregulins. In spotting lethal rats, in which functional ET(B) receptors are absent, we find accelerated expression of the Schwann cell marker S100 in developing nerves. These observations indicate that complex growth factor interactions control the timing of Schwann cell development in embryonic nerves and that ETs act as negative regulators of Schwann cell generation.
雪旺细胞前体是神经嵴的衍生物，在一个严格定时、特征明确且直接受轴突信号（特别是β-神经调节蛋白）控制的过程中产生雪旺细胞。在此，我们提供证据表明内皮素（ETs）在该系统中对细胞存活和谱系进展也很重要。我们发现ETs在不刺激DNA合成的情况下促进大鼠雪旺细胞前体在体外存活。使用ET受体激动剂和拮抗剂，我们证明ET的这一作用是由ET(B)受体介导的。逆转录聚合酶链反应（RT-PCR）显示发育中的大鼠周围神经系统（PNS）中存在ET和ET受体mRNA。我们之前表明，体外β-神经调节蛋白能按时促进雪旺细胞前体生成雪旺细胞，且这一过程可被成纤维细胞生长因子2加速。在此我们表明，尽管ETs促进前体的长期存活，但前体向雪旺细胞的转变却延迟了。此外，ETs阻断了β-神经调节蛋白的成熟作用。在斑点致死大鼠（其中不存在功能性ET(B)受体）中，我们发现在发育中的神经里雪旺细胞标志物S100的表达加速。这些观察结果表明，复杂的生长因子相互作用控制着胚胎神经中雪旺细胞发育的时间，且ETs作为雪旺细胞生成的负调节因子发挥作用。
