Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background.
Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background.
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DOI：
10.1073/pnas.95.24.14517
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发表时间：
1998-11
影响因子：
11.1
通讯作者：
Robert K. McNamara;D. Stumpo;L. Morel;Mark H. Lewis;Edward K. Wakeland;P. Blackshear;Robert H. Lenox
中科院分区：
文献类型：
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作者：
Robert K. McNamara;D. Stumpo;L. Morel;Mark H. Lewis;Edward K. Wakeland;P. Blackshear;Robert H. Lenox
肉豆蔻酰化的富含丙氨酸的C-激酶底物(MARCKS)是脑内重要的蛋白激酶C(PKC)底物，在海马颗粒细胞及其轴突苔藓纤维中高表达。在这里，我们研究了杂合子MACs突变小鼠的海马锥体下苔藓纤维(IP-MF)肢体长度和空间学习能力，与野生型对照相比，MARCKS表达减少了大约50%。在129B6(N3)背景下，与野生型对照相比，MACs突变导致IP-MF增殖，显著增加海马PKCepsilon的表达，并使空间学习熟练。然而，野生型129B6(N3)小鼠表现出与近交系129Sv小鼠相似的表型特征，包括相对于近交系C57BL/6J小鼠的IP-MF发育不良和空间反转学习障碍，这表明129Sv背景基因对野生型和可能的突变表型有显著贡献。事实上，当这些小鼠与近交系C57BL/6J小鼠回交9代以减少129Sv背景基因时，MACS突变并没有影响IP-MF长度或海马区PKCepsilon的表达，并且与野生型对照相比，空间学习受损，后者现在显示出熟练的空间学习。此外，在不同的菌株(B6SJL(N1))中，MACS突变也产生了显著的空间学习障碍，这种损害被Marcks的转基因表达逆转。综上所述，这些数据表明MACs杂合子突变改变了连锁的129Sv基因的表达(S)，影响了海马苔藓纤维的发育和空间学习成绩，并且Marcks在空间学习过程中发挥了重要作用。
The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent protein kinase C (PKC) substrate in brain that is expressed highly in hippocampal granule cells and their axons, the mossy fibers. Here, we examined hippocampal infrapyramidal mossy fiber (IP-MF) limb length and spatial learning in heterozygous Macs mutant mice that exhibit an approximately 50% reduction in MARCKS expression relative to wild-type controls. On a 129B6(N3) background, the Macs mutation produced IP-MF hyperplasia, a significant increase in hippocampal PKCepsilon expression, and proficient spatial learning relative to wild-type controls. However, wild-type 129B6(N3) mice exhibited phenotypic characteristics resembling inbred 129Sv mice, including IP-MF hypoplasia relative to inbred C57BL/6J mice and impaired spatial-reversal learning, suggesting a significant contribution of 129Sv background genes to wild-type and possibly mutant phenotypes. Indeed, when these mice were backcrossed with inbred C57BL/6J mice for nine generations to reduce 129Sv background genes, the Macs mutation did not effect IP-MF length or hippocampal PKCepsilon expression and impaired spatial learning relative to wild-type controls, which now showed proficient spatial learning. Moreover, in a different strain (B6SJL(N1), the Macs mutation also produced a significant impairment in spatial learning that was reversed by transgenic expression of MARCKS. Collectively, these data indicate that the heterozygous Macs mutation modifies the expression of linked 129Sv gene(s), affecting hippocampal mossy fiber development and spatial learning performance, and that MARCKS plays a significant role in spatial learning processes.