D'Costa A P, Prevette D M, Houenou L J, Wang S, Zackenfels K, Rohrer H, Zapf J, Caroni P, Oppenheim R W
Department of Neurobiology and Anatomy and Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
J Neurobiol. 1998 Sep 5;36(3):379-94.
During development of the avian neuromuscular system, lumbar spinal motoneurons (MNs) innervate their muscle targets in the hindlimb coincident with the onset and progression of MN programmed cell death (PCD). Paralysis (activity blockade) of embryos during this period rescues large numbers of MNs from PCD. Because activity blockade also results in enhanced axonal branching and increased numbers of neuromuscular synapses, it has been postulated that following activity blockade, increased numbers of MNs can gain access to muscle-derived trophic agents that prevent PCD. An assumption of the access hypothesis of MN PCD is the presence of an activity-dependent, muscle-derived sprouting or branching agent. Several previous studies of sprouting in the rodent neuromuscular system indicate that insulin-like growth factors (IGFs) are candidates for such a sprouting factor. Accordingly, in the present study we have begun to test whether the IGFs may play a similar role in the developing avian neuromuscular system. Evidence in support of this idea includes the following: (a) IGFs promote MN survival in vivo but not in vitro; (b) neutralizing antibodies against IGFs reduce MN survival in vivo; (c) both in vitro and in vivo, IGFs increase neurite growth, branching, and synapse formation; (d) activity blockade increases the expression of IGF-1 and IGF-2 mRNA in skeletal muscles in vivo; (e) in vivo treatment of paralyzed embryos with IGF binding proteins (IGF-BPs) that interfere with the actions of endogenous IGFs reduce MN survival, axon branching, and synapse formation; (f) treatment of control embryos in vivo with IGF-BPs also reduces synapse formation; and (g) treatment with IGF-1 prior to the major period of cell death (i.e., on embryonic day 6) increases subsequent synapse formation and MN survival and potentiates the survival-promoting actions of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) administered during the subsequent 4- to 5-day period of PCD. Collectively, these data provide new evidence consistent with the role of the IGFs as activity-dependent, muscle-derived agents that play a role in regulating MN survival in the avian embryo.
在鸟类神经肌肉系统发育过程中，腰段脊髓运动神经元（MNs）在MN程序性细胞死亡（PCD）开始和进展的同时支配后肢的肌肉靶标。在此期间对胚胎进行麻痹（活动阻断）可使大量MNs免于PCD。由于活动阻断还会导致轴突分支增强和神经肌肉突触数量增加，因此有人推测，活动阻断后，更多的MNs能够获得肌肉衍生的营养因子，从而预防PCD。MN PCD的“获得假说”的一个假设是存在一种依赖活动的、肌肉衍生的发芽或分支因子。先前对啮齿动物神经肌肉系统发芽的几项研究表明，胰岛素样生长因子（IGFs）可能是这种发芽因子的候选者。因此，在本研究中，我们开始测试IGFs在鸟类神经肌肉系统发育中是否可能发挥类似作用。支持这一观点的证据包括以下几点：（a）IGFs在体内而非体外促进MN存活；（b）针对IGFs的中和抗体可降低体内MN存活率；（c）在体外和体内，IGFs均可增加神经突生长、分支和突触形成；（d）活动阻断可增加体内骨骼肌中IGF-1和IGF-2 mRNA的表达；（e）用干扰内源性IGFs作用的IGF结合蛋白（IGF-BPs）对麻痹胚胎进行体内治疗，可降低MN存活率、轴突分支和突触形成；（f）用IGF-BPs对对照胚胎进行体内治疗也可减少突触形成；（g）在细胞死亡的主要时期之前（即胚胎第6天）用IGF-1进行治疗，可增加随后的突触形成和MN存活，并增强在随后4至5天的PCD期间给予的脑源性神经营养因子（BDNF）和胶质细胞系源性神经营养因子（GDNF）的存活促进作用。总的来说，这些数据提供了新的证据，支持IGFs作为依赖活动的、肌肉衍生的因子在调节鸟类胚胎MN存活中发挥作用的观点。
