Morrissey T K, Levi A D, Nuijens A, Sliwkowski M X, Bunge R P
Miami Project to Cure Paralysis, University of Miami School of Medicine, FL 33136.
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1431-5. doi: 10.1073/pnas.92.5.1431.
The ability of sensory axons to stimulate Schwann cell proliferation by contact was established in the 1970s. Although the mitogen responsible for this proliferation has been localized to the axon surface and biochemically characterized, it has yet to be identified. Recently a family of proteins known as heregulins (HRGs) has been isolated, characterized, and shown to interact with a number of class 1 receptor tyrosine kinases, including the erbB2, erbB3, and erbB4 gene products. These factors include glial growth factor, a Schwann cell mitogen. We have tested the effects of antibodies against components of this system (HRG beta 1 and p185erbB2) in cocultures of rat sensory neurons and human (or rat) Schwann cells to elucidate the role of these proteins in axon-induced Schwann cell proliferation. 2C4, a monoclonal antibody specific for the human p185erbB2 receptor tyrosine kinase, bound to the surface of human Schwann cells and reduced human Schwann cell incorporation of [3H]thymidine by > 90% compared with untreated controls in this coculture system. This antibody had no effect on rat Schwann cell incorporation of [3H]thymidine under similar conditions. A polyclonal antibody raised against HRG beta 1 reduced human and rat Schwann cell incorporation of [3H]thymidine by nearly 80% and up to 49%, respectively, relative to controls. These results imply that a HRG, or a HRG-like molecule, is a component of the axonal mitogen. This mitogen is presented to Schwann cells by axons and induces proliferation through an interaction that involves p185erbB2 on Schwann cells.
感觉轴突通过接触刺激施万细胞增殖的能力在20世纪70年代就已得到证实。尽管负责这种增殖的促有丝分裂原已定位在轴突表面并进行了生化特性分析，但尚未被鉴定出来。最近，一个被称为神经调节蛋白（HRGs）的蛋白质家族已被分离、鉴定，并显示与多种1类受体酪氨酸激酶相互作用，包括erbB2、erbB3和erbB4基因产物。这些因子包括神经胶质生长因子，一种施万细胞促有丝分裂原。我们在大鼠感觉神经元与人类（或大鼠）施万细胞的共培养中测试了针对该系统成分（HRGβ1和p185erbB2）的抗体的作用，以阐明这些蛋白质在轴突诱导的施万细胞增殖中的作用。2C4是一种针对人类p185erbB2受体酪氨酸激酶的单克隆抗体，在该共培养系统中，它与人类施万细胞表面结合，并使人类施万细胞对[3H]胸腺嘧啶核苷的掺入量比未处理的对照减少了90%以上。在类似条件下，该抗体对大鼠施万细胞对[3H]胸腺嘧啶核苷的掺入没有影响。相对于对照，针对HRGβ1产生的多克隆抗体分别使人类和大鼠施万细胞对[3H]胸腺嘧啶核苷的掺入量减少了近80%和高达49%。这些结果表明，一种HRG或一种HRG样分子是轴突促有丝分裂原的一个成分。这种促有丝分裂原由轴突呈递给施万细胞，并通过涉及施万细胞上p185erbB2的相互作用诱导增殖。
