Replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence creates murine model of major depressive disorder.
Replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence creates murine model of major depressive disorder.
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DOI：
10.1002/ajmg.b.31197
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发表时间：
2011-07
影响因子：
2.8
通讯作者：
Hughes, Hugh B., III
中科院分区：
文献类型：
--
作者：
Zubenko, George S.;Hughes, Hugh B., III
重度抑郁症（MDD）是世界范围内导致残疾的主要原因。复发性早发性MDD（RE-MDD）是MDD的一种严重的家族性形式，其家族为识别和表征赋予MDD和相关疾病易感性的遗传变异提供了重要资源。先前的研究发现，在人CREB 1启动子内存在一种罕见的、高度渗透的A（-115）G转换，该转换在体外降低了启动子活性，并与RE-MDD家族中的抑郁症相关。基于病因学的MDD重组动物模型的开发将促进我们对MDD病理生理学的有限理解的进步，以及改进治疗的发展。在这里，我们报告了一个同源突变C57 BL/6 NTac小鼠模型，携带人类致病序列在小鼠Creb 1启动子的同源位置的建设和初步表征。重组菌株表现出生殖能力和幼崽存活率下降，这可能与RE-MDD家族中观察到的婴儿死亡率增加有关;脑室扩大;小鼠大脑皮层中CREB蛋白水平降低，如采用致病性人CREB 1启动子的转染实验所预测的那样;以及两个标准化行为测试（强迫游泳和大理石掩埋测试）的改变。这些初步发现支持人A（-115）G启动子变体的致病性，并邀请进一步表征这种基于病因学的MDD重组动物模型。对疾病表达具有高度渗透作用的人启动子变体为创建基于病因学的人类疾病小鼠模型提供了有吸引力的机会，同时对小鼠基因组的破坏最小。
Major Depressive Disorder (MDD) is a leading cause of disability worldwide. Families with Recurrent, Early-Onset MDD (RE-MDD), a severe, familial form of MDD, have provided an important resource for identifying and characterizing genetic variants that confer susceptibility to MDD and related disorders. Previous studies identified a rare, highly penetrant A(-115)G transition within the human CREB1 promoter that reduced promoter activity in vitro and was associated with depressive disorders in RE-MDD families. The development of an etiology-based recombinant animal model for MDD would facilitate the advancement of our limited understanding of the pathophysiology of MDD, as well as the development of improved treatments. Here we report the construction and initial characterization of a congenic mutant C57BL/6NTac mouse model that carries the human pathogenic sequence at the homologous position of the mouse Creb1 promoter. The recombinant strain exhibited decreases in reproductive capacity and pup survival that may be related to increased infant mortality observed in RE-MDD families; enlargement of the cerebral ventricles; reduced levels of CREB protein in the mouse cerebral cortex, as predicted from transfection experiments employing the pathogenic human CREB1 promoter; and alterations in two standardized behavioral tests, the forced swim and marble burying tests. These initial findings support the pathogenicity of the human A(-115)G promoter variant, and invite further characterization of this etiology-based recombinant animal model for MDD. Human promoter variants that have highly penetrant effects on disease expression provide an attractive opportunity for creating etiology-based mouse models of human diseases, with minimal disruption of the mouse genome.
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DOI：
10.1002/ajmg.10158
发表时间：
2002-03-08
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
Maher, BS;Marazita, ML;Zubenko, GS
通讯作者：
Zubenko, GS
影响因子：
5
作者：
BROEKKAMP, CL;RIJK, HW;LLOYD, KL
通讯作者：
LLOYD, KL
DOI：
10.1007/bf01272765
发表时间：
1990-01-01
期刊：
JOURNAL OF NEURAL TRANSMISSION-GENERAL SECTION
影响因子：
--
作者：
LECCI, A;BORSINI, F;MELI, A
通讯作者：
MELI, A
影响因子：
2.9
作者：
BERNARDI, M;VERGONI, AV;BERTOLINI, A
通讯作者：
BERTOLINI, A
影响因子：
30.8
作者：
Le, WD;Xu, PY;Vassilatis, DK
通讯作者：
Vassilatis, DK