Stottmann Rolf W, Choi Murim, Mishina Yuji, Meyers Erik N, Klingensmith John
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Development. 2004 May;131(9):2205-18. doi: 10.1242/dev.01086. Epub 2004 Apr 8.
The neural crest is a multipotent, migratory cell population arising from the border of the neural and surface ectoderm. In mouse, the initial migratory neural crest cells occur at the five-somite stage. Bone morphogenetic proteins (BMPs), particularly BMP2 and BMP4, have been implicated as regulators of neural crest cell induction, maintenance, migration, differentiation and survival. Mouse has three known BMP2/4 type I receptors, of which Bmpr1a is expressed in the neural tube sufficiently early to be involved in neural crest development from the outset; however, earlier roles in other domains obscure its requirement in the neural crest. We have ablated Bmpr1a specifically in the neural crest, beginning at the five-somite stage. We find that most aspects of neural crest development occur normally; suggesting that BMPRIA is unnecessary for many aspects of early neural crest biology. However, mutant embryos display a shortened cardiac outflow tract with defective septation, a process known to require neural crest cells and to be essential for perinatal viability. Surprisingly, these embryos die in mid-gestation from acute heart failure, with reduced proliferation of ventricular myocardium. The myocardial defect may involve reduced BMP signaling in a novel, minor population of neural crest derivatives in the epicardium, a known source of ventricular myocardial proliferation signals. These results demonstrate that BMP2/4 signaling in mammalian neural crest derivatives is essential for outflow tract development and may regulate a crucial proliferation signal for the ventricular myocardium.
神经嵴是一种多能性的迁移细胞群，起源于神经外胚层和表面外胚层的边界。在小鼠中，最初迁移的神经嵴细胞出现在五体节阶段。骨形态发生蛋白（BMP），特别是BMP2和BMP4，被认为是神经嵴细胞诱导、维持、迁移、分化和存活的调节因子。小鼠有三种已知的BMP2/4 I型受体，其中Bmpr1a在神经管中表达得足够早，从一开始就参与神经嵴的发育；然而，它在其他区域的早期作用掩盖了其在神经嵴中的需求。我们从五体节阶段开始，在神经嵴中特异性地敲除Bmpr1a。我们发现神经嵴发育的大多数方面都正常发生；这表明BMPRIA对早期神经嵴生物学的许多方面是不必要的。然而，突变胚胎显示出心脏流出道缩短，伴有间隔缺陷，这一过程已知需要神经嵴细胞，并且对围产期生存至关重要。令人惊讶的是，这些胚胎在妊娠中期死于急性心力衰竭，心室心肌的增殖减少。心肌缺陷可能涉及心外膜中一小部分新的神经嵴衍生物中BMP信号的减少，心外膜是已知的心室心肌增殖信号的来源。这些结果表明，哺乳动物神经嵴衍生物中的BMP2/4信号对于流出道发育至关重要，并且可能调节心室心肌的关键增殖信号。
