Myristoylated alanine‐rich C‐kinase substrate (MARCKS) is an intracellular receptor for polysialic acid. MARCKS supports development, synaptic plasticity, and regeneration after injury. MARCKS binds with its functionally essential effector domain (ED) to polysialic acid. A 25‐mer peptide comprising the ED of MARCKS stimulates neuritogenesis of primary hippocampal neurons after addition to the culture. This motivated us to investigate whether ED peptide has similar effects in spinal cord injury. ED peptide supported recovery and regrowth of monoaminergic axons in female, but not in male mice. Sex‐specific differences in response to ED peptide application also occurred in cultured neurons. In female but not male neurons, the ED peptide enhanced neurite outgrowth that could be suppressed by inhibitors of the estrogen receptors α and β, fibroblast growth factor receptor‐1, protein kinase C, and matrix metalloproteinase 2. In addition, we observed female‐specific elevation of phosphorylated MARCKS levels after ED peptide treatment. In male neurons, the ED peptide enhanced neuritogenesis in the presence of an androgen receptor inhibitor to the extent seen in ED peptide‐treated female neurons. However, inhibition of androgen receptor did not lead to increased phosphorylation of MARCKS. These results provide insights into the functions of a novel compound contributing to gender‐dependent regeneration.

中文翻译：

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肉豆蔻酰化富含丙氨酸的 C 激酶底物效应域肽改善脊髓损伤后的性别特异性恢复和轴突再生

肉豆蔻酰化的富含丙氨酸的 C 激酶底物 (MARCKS) 是聚唾液酸的细胞内受体。MARCKS 支持损伤后的发育、突触可塑性和再生。MARCKS 以其功能必需的效应结构域 (ED) 与聚唾液酸结合。包含 MARCKS ED 的 25 聚体肽在添加到培养物中后刺激原代海马神经元的神经发生。这促使我们研究 ED 肽是否在脊髓损伤中具有类似的作用。ED 肽支持雌性单胺能轴突的恢复和再生，但不支持雄性小鼠。对 ED 肽应用的反应的性别特异性差异也发生在培养的神经元中。在雌性而非雄性神经元中，ED 肽增强了神经突的生长，而这种生长可以被雌激素受体 α 和 β 的抑制剂抑制，成纤维细胞生长因子受体 1、蛋白激酶 C 和基质金属蛋白酶 2。此外，我们观察到 ED 肽处理后磷酸化 MARCKS 水平的女性特异性升高。在雄性神经元中，ED 肽在雄激素受体抑制剂存在的情况下增强了神经发生，达到了在 ED 肽处理的女性神经元中所见。然而，雄激素受体的抑制不会导致 MARCKS 的磷酸化增加。这些结果提供了对有助于性别依赖性再生的新型化合物功能的见解。在雄激素受体抑制剂存在的情况下，ED 肽增强了神经发生作用，达到了在 ED 肽处理的雌性神经元中所见的程度。然而，雄激素受体的抑制不会导致 MARCKS 的磷酸化增加。这些结果提供了对有助于性别依赖性再生的新型化合物功能的见解。在雄激素受体抑制剂存在的情况下，ED 肽增强了神经发生作用，达到了在 ED 肽处理的雌性神经元中所见的程度。然而，雄激素受体的抑制不会导致 MARCKS 的磷酸化增加。这些结果提供了对有助于性别依赖性再生的新型化合物功能的见解。