INSERM U 839, Paris F-75005, France; Université Pierre et Marie Curie-Paris6, UMR S839, Paris F-75005, France; Institut du Fer à Moulin, Paris F-75005, France.
Prog Neurobiol. 2015 Mar;126:1-18. doi: 10.1016/j.pneurobio.2014.09.002. Epub 2014 Oct 16.
Nervous system development, plasticity and regeneration require numerous, coordinated and finely tuned subcellular mechanisms. Phosphoproteins of the stathmin family, originally identified as intracellular signal relay proteins, are mostly or exclusively expressed in the nervous system with a high level of expression during brain development. Vertebrate stathmins 1-4 all possess a C-terminal "stathmin-like domain" that binds or releases tubulin in a phosphorylation dependent way, and hence participates in the control of microtubule dynamics, an essential process for neuronal differentiation. Contrary to stathmin 1, stathmins 2-4 possess an N-terminal extension whose reversible palmitoylation specifically targets them to the Golgi and intracellular membranes. Regulation of stathmins 2-4 palmitoylation is therefore an important regulatory mechanism that controls their shuttling to various neuronal compartments where they can then act locally. Expression of stathmins is upregulated during neuronal differentiation and plasticity, and altered in numerous neurodegenerative diseases. Experimental perturbation of stathmins expression in Drosophila or in neurons in culture revealed their importance in neuronal growth and differentiation, each stathmin fulfilling at least partially distinct and likely complementary roles. On the other hand, knock-out of stathmins in mice, with the exception of stathmin 2, resulted in mostly mild or no detected phenotype, revealing likely compensations among stathmins. Altogether, through their combinatorial expression and regulation by phosphorylation and by palmitoylation, and through their interactions with tubulin and other neuronal protein targets, the various stathmins appear as essential regulators of neuronal differentiation at the various stages during development and plasticity of the nervous system.
神经系统的发育、可塑性和再生需要许多协调和精细调节的亚细胞机制。最初被鉴定为细胞内信号转导蛋白的 stathmin 家族的磷酸化蛋白主要或完全在神经系统中表达,在大脑发育过程中表达水平很高。脊椎动物的 stathmin 1-4 都具有 C 端“stathmin 样结构域”,该结构域以磷酸化依赖的方式结合或释放微管蛋白,从而参与微管动力学的控制,这是神经元分化的一个基本过程。与 stathmin 1 不同,stathmin 2-4 具有 N 端延伸,其可逆棕榈酰化特异性将它们靶向高尔基体和细胞内膜。因此,stathmin 2-4 的棕榈酰化调节是控制它们向各种神经元区室穿梭的重要调节机制,在这些区室中,它们可以局部发挥作用。stathmin 的表达在神经元分化和可塑性过程中上调,并且在许多神经退行性疾病中改变。在果蝇或培养神经元中实验性地扰动 stathmin 的表达揭示了它们在神经元生长和分化中的重要性,每种 stathmin 至少部分地履行了不同且可能互补的作用。另一方面,除了 stathmin 2 之外,在小鼠中敲除 stathmin 导致的表型大多是轻微的或没有检测到的,这表明 stathmin 之间可能存在代偿作用。总之,通过它们的组合表达和磷酸化和棕榈酰化调节,以及与微管蛋白和其他神经元蛋白靶标的相互作用,各种 stathmin 似乎是神经系统发育和可塑性过程中神经元分化的重要调节因子。