Cann G M, Lee J W, Stockdale F E
Department of Medicine, Stanford University, CA 94305-5115, USA.
Anat Embryol (Berl). 1999 Sep;200(3):239-52. doi: 10.1007/s004290050276.
Primary skeletal muscle fibers first form in the segmented portions of paraxial mesoderm called somites. Although the neural tube and notochord are recognized as crucial in patterning myogenic cell lineages during avian and mammalian somitic myogenesis, the source, identities, and actions of the signals governing this process remain controversial. It has been shown that signals emanating from the ventral neural tube and/or notochord alone or Shh alone serve to activate MyoD expression in somites. However, beyond a role in initiating MyoD expression, little is known about the effects of Shh on primary muscle fiber formation in somites of higher vertebrates. The studies reported here investigate how the ventral neural tube promotes myogenesis and compare the effects of the ventral neural tube with those of purified Shh protein on fiber formation in somites. We show that purified Shh protein mimics actions of the ventral neural tube on somites including initiation of muscle fiber formation, enhancement of numbers of primary muscle fibers, and particularly, the formation of primary fibers that express slow myosin. There is a marked increase in slow myosin expression in fibers in response to Shh as somites mature. The effects of ventral neural tube on fiber formation can be blocked by disrupting the Shh signaling pathway by increasing the activity of somitic cyclic AMP-dependent protein kinase A. Furthermore, it was demonstrated that apoptosis is a dominant fate of somite cells, but not somitic muscle fibers, when cultured in the absence of the neural tube, and that application of Shh protein to somites reduced apoptosis. The block to apoptosis by Shh is a manifestation of the maturity of the somite with a progressive increase in the block as somites are displaced rostrally from somite III forward. We conclude that purified Shh protein in mimicking the effects of the ventral neural tube on segmented mesoderm can exert pleiotropic effects during primary myogenesis, including: control of the proliferative expansion of myogenic progenitor cells, antagonism of cell death pathways within the precursors to muscle fibers, and during the crucial process of primary myogenesis, can exert an effect on diversification of muscle fiber types.
原发性骨骼肌纤维最初在称为体节的轴旁中胚层的节段部分形成。尽管神经管和脊索在鸟类和哺乳动物体节性肌生成过程中对成肌细胞谱系的模式形成至关重要，但控制这一过程的信号的来源、特性和作用仍存在争议。研究表明，仅来自腹侧神经管和/或脊索的信号或单独的音猬因子（Shh）可激活体节中的肌分化抗原（MyoD）表达。然而，除了在启动MyoD表达方面的作用外，关于Shh对高等脊椎动物体节中初级肌纤维形成的影响知之甚少。本文报道的研究调查了腹侧神经管如何促进肌生成，并比较了腹侧神经管与纯化的Shh蛋白对体节中纤维形成的影响。我们发现，纯化的Shh蛋白模拟腹侧神经管对体节的作用，包括启动肌纤维形成、增加初级肌纤维数量，特别是形成表达慢肌球蛋白的初级纤维。随着体节成熟，纤维中慢肌球蛋白的表达因Shh而显著增加。通过增加体节环磷酸腺苷依赖性蛋白激酶A的活性来破坏Shh信号通路，可阻断腹侧神经管对纤维形成的影响。此外，研究表明，在没有神经管的情况下培养时，细胞凋亡是体节细胞而非体节肌纤维的主要命运，并且将Shh蛋白应用于体节可减少细胞凋亡。Shh对细胞凋亡的阻断是体节成熟的一种表现，随着体节从第三体节向前端移位，这种阻断作用逐渐增强。我们得出结论，纯化的Shh蛋白在模拟腹侧神经管对节段性中胚层的作用时，可在初级肌生成过程中发挥多效性作用，包括：控制成肌祖细胞的增殖扩增、拮抗肌纤维前体细胞内的细胞死亡途径，以及在初级肌生成的关键过程中，对肌纤维类型的多样化产生影响。
