NEUROBIOLOGY OF MARCKS--A MACS MUTANT MOUSE MODEL

马克斯的神经生物学——MACS突变小鼠模型

• 批准号: 6186780
• 负责人: Robert H. Lenox
• 金额: $ 24.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-10 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6186780
• 关键词: alanine; biological signal transduction; electrophysiology; enzyme substrate; fatty acylation; gene expression; genotype; hippocampus; laboratory mouse; learning; long term potentiation; membrane activity; memory; model design /development; mossy fiber; myristates; neural plasticity; neurobiology; polymerase chain reaction; protein kinase C; quantitative trait loci; visual perception

MARCKS (Myristoylated Alanine Rich C Kinase Substrate) is the most prominent phosphoprotein substrate for protein kinase C in brain. Accumulating data have indicated a role for MARCKS in transducing extracellular signals for the regulation of actin-membrane plasticity and cellular processes associated with dynamic regulation of the neuronal cytoskeleton and synaptic restructuring, e.g., brain development and neurotransmitter signaling. Additional evidence from our laboratory has demonstrated a role for MARCKS in the hippocampus as a target for the long-term action of chronic lithium in the brain. With the recent creation of a mutant mouse model for the Macs gene which has now been backcrossed onto a C57BL/6 background to the eighth generation, MARCKS has been shown to play a critical role in brain development. Recent data from our laboratory have demonstrated for the first time that the distribution of MARCKS mRNA in brain is preferentially expressed in limbic and limbic-related regions of the brain, with a specific cellular distribution in hippocampus of both rat and mouse brain. In preliminary data, we have also demonstrated that MARCKS is expressed in a gene-dose dependent fashion in adult Macs null/+ heterozygotes, and that the approximately 50 percent reduction of MARCKS expression is associated with hippocampal mossy fiber hyperplasia, as well as enhanced spatial learning (Sections C.8b and C.9). These findings take on further significance in light of our current additional data demonstrating that DBA/2 mice which demonstrate hippocampal mossy fiber hypoplasia and significant spatial learning deficits, also show a significant elevation in hippocampal MARCKS as compared to C57BL/6 mice. This proposal outlines a three year interdisciplinary research strategy, in conjunction with the Center for Mammalian Genetics, to create mice expressing levels of MARCKS varying from 50 percent (Macs null/+) to 260 percent (MARCKS Tg+/+) of that expressed by wild-type mice. In these mice we will investigate the functional consequences of both under and over-expression of MARCKS on hippocampal mossy fiber development, hippocampal LTP electrophysiology, and spatial learning. In addition, we will assess the genetic basis of this interstrain variation in MARCKS expression and identify the positions of quantitative trait loci controlling MARCKS expression among backcross and/or F2 intercross progeny of DBA/2 and C57BL/6. Once the genetic basis of this variation is evident, we will determine if the same loci cosegregate with the length of the mossy fiber infrapyramidal projection and spatial learning in hybrid progeny expressing highest vs. lowest MARCKS. The outlined series of studies are designed to examine a direct role for MARCKS in neuroplastic events in brain related to hippocampal development and learning/memory, and assess the extent to which these complex phenotypic traits are linked to the Macs gene itself and/or interactive gene modifiers.

MARCKS（肉豆蔻酰化丙氨酸富C激酶底物）是最 脑中蛋白激酶 C 的重要磷蛋白底物。 积累的数据表明 MARCKS 在转导中的作用 调节肌动蛋白膜可塑性的细胞外信号 和与动态调节相关的细胞过程 神经元细胞骨架和突触重组，例如大脑 发育和神经递质信号传导。 额外的证据来自 我们的实验室已经证明了 MARCKS 在海马体中的作用： 锂在大脑中长期作用的目标。 和 最近创建了 Macs 基因突变小鼠模型， 现在已回交至 C57BL/6 背景至第八代， MARCKS 已被证明在大脑发育中发挥着关键作用。 我们实验室的最新数据首次证明 MARCKS mRNA在大脑中的分布优先 在大脑边缘和边缘相关区域表达， 大鼠和小鼠海马的特定细胞分布 脑。 在初步数据中，我们还证明了 MARCKS 在成人 Mac 中以基因剂量依赖性方式表达 null/+ 杂合子，并且 MARCKS 减少了大约 50% 表达与海马苔藓纤维增生有关，如 以及增强的空间学习（C.8b 和 C.9 节）。 这些 鉴于我们目前的额外情况，调查结果具有进一步的意义 数据表明 DBA/2 小鼠表现出海马苔藓 纤维发育不全和显着的空间学习缺陷也显示 与 C57BL/6 相比，海马 MARCKS 显着升高 老鼠。该提案概述了为期三年的跨学科研究 与哺乳动物遗传学中心合作的战略， 创建表达 MARCKS 水平从 50% 到 50% 不等的小鼠（Macs null/+) 至野生型表达量的 260% (MARCKS Tg+/+) 老鼠。 在这些小鼠中，我们将研究以下功能的后果： 海马苔藓纤维上 MARCKS 的过表达和过表达 发育、海马 LTP 电生理学和空间学习。 此外，我们将评估这种间系的遗传基础 MARCKS 表达​​的变化并确定 控制回交中 MARCKS 表达​​的数量性状位点 和/或DBA/2和C57BL/6的F2杂交后代。 一旦遗传 这种变异的基础是明显的，我们将确定是否有相同的基因座 与苔藓纤维锥体下投影的长度共分离 以及表达最高与最低的杂交后代的空间学习 马克斯。 概述的一系列研究旨在检验直接 MARCKS 在与海马相关的大脑神经塑性事件中的作用 发展和学习/记忆，并评估这些的程度 复杂的表型性状与 Macs 基因本身和/或 交互基因修饰剂。

项目成果

Differential changes in the phosphorylation of the protein kinase C substrates myristoylated alanine-rich C kinase substrate and growth-associated protein-43/B-50 following Schaffer collateral long-term potentiation and long-term depression.

Schaffer 侧支长期增强和长期抑制后，蛋白激酶 C 底物、肉豆蔻酰化富含丙氨酸的 C 激酶底物和生长相关蛋白 43/B-50 的磷酸化存在差异变化。

• 发表时间: 1999
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Ramakers,GM;McNamara,RK;Lenox,RH;DeGraan,PN
• 通讯作者: DeGraan,PN

Transcriptional regulation of mouse MARCKS promoter in immortalized hippocampal cells.

永生化海马细胞中小鼠 MARCKS 启动子的转录调控。

• DOI: 10.1006/bbrc.2002.6655
• 发表时间: 2002
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Wang,Le;Liu,Xingge;Lenox,RobertH
• 通讯作者: Lenox,RobertH

Differential expression and regulation of myristoylated alanine-rich C kinase substrate (MARCKS) in the hippocampus of C57/BL6J and DBA/2J mice.

C57/BL6J 和 DBA/2J 小鼠海马中肉豆蔻酰化富含丙氨酸的 C 激酶底物 (MARCKS) 的差异表达和调节。

• DOI: 10.1046/j.1471-4159.2003.01700.x
• 发表时间: 2003
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: McNamara,RobertK;Vasquez,PatriciaA;Mathe,AleksanderA;Lenox,RobertH
• 通讯作者: Lenox,RobertH

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.

• DOI: 10.1073/pnas.95.24.14517
• 发表时间: 1998-11
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Robert K. McNamara;D. Stumpo;L. Morel;Mark H. Lewis;Edward K. Wakeland;P. Blackshear;Robert H. Lenox

Facial motor neuron regeneration induces a unique spatial and temporal pattern of myristoylated alanine-rich C kinase substrate expression.

面部运动神经元再生诱导肉豆蔻酰化富含丙氨酸的 C 激酶底物表达的独特空间和时间模式。

• DOI: 10.1016/s0306-4522(00)00039-7
• 发表时间: 2000
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: McNamara,RK;Jiang,Y;Streit,WJ;Lenox,RH
• 通讯作者: Lenox,RH