The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation
The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation
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DOI：
10.1101/gad.10.7.816
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发表时间：
1996-04-01
影响因子：
10.5
通讯作者：
Tsai, LH
中科院分区：
文献类型：
--
作者：
Nikolic, M;Dudek, H;Tsai, LH
细胞周期蛋白依赖性激酶5（cdk 5）与cdk家族中已知在增殖细胞中起作用的其他成员高度同源。尽管结构相似，cdk 5相关的组蛋白H1激酶活性仅在中枢神经系统（CNS）的有丝分裂后神经元中检测到。p35是神经元特异性CDK 5调节剂，其在缔合时激活CDK 5激酶活性。cdk 5/p35激酶活性在CNS神经发生的进展过程中增加，表明cdk 5在神经元分化中的功能。在这里，我们表明，cdk 5和p35蛋白都存在于发育中的神经元的生长锥。cdk 5在生长锥中的染色模式与肌动蛋白丝相似，但与微管不同。为了解决cdk 5/p35激酶在神经发生中的功能意义，我们异位表达的野生型或突变体激酶在皮层文化。cdk 5显性失活突变体（cdk 5 N（144）和cdk 5 T（33））的表达抑制了神经突的生长，而野生型蛋白的共表达挽救了这种生长。通过转染反义p35构建体获得了类似程度的轴突生长抑制，而反义p35构建体仅通过p35而不是cdk 5共表达来拯救。相比之下，在共表达外源性cdk 5和p35的神经元中，神经突起更长。这些观察结果表明，cdk 5/p35激酶在神经元分化过程中的轴突生长中起着关键作用。
Cyclin-dependent kinase 5 (cdk5) is highly homologous to other members of the cdk family that are known to function in proliferating cells. Despite the structural similarity, cdk5-associated histone H1 kinase activity is only detectable in postmitotic neurons of the central nervous system (CNS). p35 is a neuronal specific cdk5 regulator that activates cdk5 kinase activity upon association. The cdk5/p35 kinase activity increases during the progression of CNS neurogenesis, suggesting a function of cdk5 in neuronal differentiation. Here we show that both cdk5 and p35 proteins are present in the growth cones of developing neurons. The staining pattern of cdk5 in the growth cones is similar to that of actin filaments but not microtubules. To address the functional significance of the cdk5/p35 kinase in neurogenesis, we ectopically expressed wild-type or mutant kinases in cortical cultures. Expression of dominant-negative mutants of cdk5 (Cdk5N(144) and cdk5T(33)) inhibited neurite outgrowth, which was rescued by coexpression of the wild-type proteins. A similar extent of neurite outgrowth inhibition was obtained by transfection of an antisense p35 construct, which in turn was only rescued by p35 but not cdk5 coexpression. In contrast, longer neurites were elaborated in neurons that coexpressed exogenous cdk5 and p35. These observations suggest that the cdk5/p35 kinase plays a critical role in neurite outgrowth during neuronal differentiation.