Isozyme-Specific Role of SAD-A in Neuronal Migration During Development of Cerebral Cortex
Isozyme-Specific Role of SAD-A in Neuronal Migration During Development of Cerebral Cortex
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DOI：
10.1093/cercor/bhy253
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发表时间：
2019-09-01
期刊：
影响因子：
3.7
通讯作者：
Nakanishi, Makoto
中科院分区：
文献类型：
--
作者：
Nakanishi, Keiko;Niida, Hiroyuki;Nakanishi, Makoto
SAD 激酶调节突触前囊泡聚集和神经元极化。之前的一份报告表明，Sada（-/-）和Sadb（-/-）双突变小鼠表现出围产期致死性，轴突/树突分化存在严重缺陷，但它们的单突变体却没有。这些结果表明它们在功能上是冗余的。令人惊讶的是，我们表明在 C57BL/6N 背景下，SAD-A 对于皮质发育至关重要，而 SAD-B 是可有可无的。 Sada(-/-)小鼠在出生后几天内死亡。它们的皮质分层模式杂乱无章，皮质神经元的径向迁移受到干扰。使用 BrdU 进行的出生日期分析和使用 pCAG-EGFP 载体进行的子宫内电穿孔分析显示，Sada(-/-) 小鼠的皮质神经元向软脑膜表面的迁移延迟。这些小鼠的延时成像证实了皮质板的缓慢迁移速度。虽然Sada(-/-)小鼠海马神经元的神经突最终可以在培养物中分化形成轴突和树突，但其轴突的平均长度比野生型短。因此，对不同于最初使用的遗传背景的分析揭示了 SAD-A 在神经元迁移和分化中的非冗余作用。
SAD kinases regulate presynaptic vesicle clustering and neuronal polarization. A previous report demonstrated that Sada(-/-) and Sadb(-/-) double-mutant mice showed perinatal lethality with a severe defect in axon/dendrite differentiation, but their single mutants did not. These results indicated that they were functionally redundant. Surprisingly, we show that on a C57BL/6N background, SAD-A is essential for cortical development whereas SAD-B is dispensable. Sada(-/-) mice died within a few days after birth. Their cortical lamination pattern was disorganized and radial migration of cortical neurons was perturbed. Birth date analyses with BrdU and in utero electroporation using pCAG-EGFP vector showed a delayed migration of cortical neurons to the pial surface in Sada(-/-) mice. Time-lapse imaging of these mice confirmed slow migration velocity in the cortical plate. While the neurites of hippocampal neurons in Sada(-/-) mice could ultimately differentiate in culture to form axons and dendrites, the average length of their axons was shorter than that of the wild type. Thus, analysis on a different genetic background than that used initially revealed a nonredundant role for SAD-A in neuronal migration and differentiation.