Carroll S L, Miller M L, Frohnert P W, Kim S S, Corbett J A
Division of Neuropathology, Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 1997 Mar 1;17(5):1642-59. doi: 10.1523/JNEUROSCI.17-05-01642.1997.
Schwann cell dedifferentiation and proliferation is a prerequisite to axonal regeneration in the injured peripheral nervous system. The neuregulin (NRG) family of growth and differentiation factors may play a particularly important role in this process, because these axon-associated molecules are potent Schwann cell mitogens and differentiation factors in vitro. We have examined Schwann cell DNA synthesis and the expression of NRGs and their receptors, the erbB membrane tyrosine kinases, in rat sciatic nerve, sensory ganglia, and spinal cord 0-30 d postaxotomy. Analysis of NRG cDNAs from these tissues revealed several novel splice variants and showed that cells endogenous to injured nerve express NRG mRNAs. A selective induction of mRNAs encoding the glial growth factor (GGF) subfamily of NRGs occurs in nerve beginning 3 d postaxotomy and thus coincides with the onset of Schwann cell DNA synthesis. In later stages of Wallerian degeneration, however, Schwann cell mitogenesis markedly decreases, whereas elevated GGF expression persists. Of the four known erbB kinases, Schwann cells express both erbB2 and erbB3 receptors over the entire interval studied. Expression of erbB2 and erbB3 is coordinately induced in response to axotomy, indicating that Schwann cell responses to NRGs may be modulated by changes in receptor density. Neuregulin (including transmembrane precursors) and erbB protein are associated with Schwann cells postaxotomy. Thus, in contrast to the concept of NRGs as axon-associated mitogens, our findings suggest that NRGs produced by Schwann cells themselves may be partially responsible for Schwann cell proliferation during Wallerian degeneration, probably acting via autocrine or paracrine mechanisms.
施万细胞去分化和增殖是受损周围神经系统轴突再生的前提条件。神经调节蛋白（NRG）家族的生长和分化因子可能在此过程中发挥特别重要的作用，因为这些与轴突相关的分子在体外是强大的施万细胞促有丝分裂原和分化因子。我们检测了大鼠坐骨神经、感觉神经节和脊髓在轴突切断后0 - 30天内施万细胞的DNA合成以及NRGs及其受体erbB膜酪氨酸激酶的表达。对来自这些组织的NRG cDNAs分析揭示了几种新的剪接变体，并表明受损神经内源性细胞表达NRG mRNAs。编码NRGs的胶质生长因子（GGF）亚家族的mRNA在轴突切断后3天开始在神经中选择性诱导产生，因此与施万细胞DNA合成的开始时间一致。然而，在华勒氏变性的后期，施万细胞的有丝分裂明显减少，而GGF表达持续升高。在四种已知的erbB激酶中，施万细胞在整个研究期间都表达erbB2和erbB3受体。erbB2和erbB3的表达在轴突切断后协同诱导，表明施万细胞对NRGs的反应可能受受体密度变化的调节。轴突切断后，神经调节蛋白（包括跨膜前体）和erbB蛋白与施万细胞相关。因此，与NRGs作为轴突相关促有丝分裂原的概念相反，我们的研究结果表明，施万细胞自身产生的NRGs可能部分负责华勒氏变性期间施万细胞的增殖，可能通过自分泌或旁分泌机制发挥作用。
