Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.
Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.
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DOI：
10.1371/journal.pone.0012278
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发表时间：
2010-08-20
期刊：
影响因子：
3.7
通讯作者：
Beaudet AL
中科院分区：
文献类型：
--
作者：
Jiang YH;Pan Y;Zhu L;Landa L;Yoo J;Spencer C;Lorenzo I;Brilliant M;Noebels J;Beaudet AL
Angelman综合征（AS）是一种神经行为障碍，与精神发育迟滞、缺乏语言发育、特征性脑电图（EEG）异常和癫痫、快乐性格、运动或平衡障碍以及自闭症行为相关。AS潜在的分子缺陷是异质性的，包括染色体15 q11-q13的大量母系缺失（70%），染色体15的父系单亲二体性（UPD）（5%），印记突变（罕见）和E6-AP泛素连接酶基因UBE 3A突变（15%）。尽管UBE 3A突变患者具有广泛的神经系统表型，但其特征通常比15 q11-q13缺失的AS患者更温和。使用染色体工程策略，我们产生了从Ube 3a到Gabrb 3的1.6-Mb染色体缺失的突变小鼠，其使Ube 3a和Gabrb 3基因失活并缺失Atp 10a基因。纯合缺失突变小鼠在围产期死于Gabrb 3基因无效突变导致的腭裂。母体缺失（m−/p+）的小鼠是可以存活的，并且没有任何明显的发育缺陷。对母本和父本缺失小鼠的表达分析证实，Ube 3a基因在脑中是母系表达的，并且表明Atp 10a和Gabrb 3基因在所研究的所有脑亚区中是双等位基因表达的。母体（m−/p+）而非父体（m+/p−）缺失小鼠的自发性癫痫发作活动增加，EEG异常。广泛的行为分析显示，在运动功能，学习和记忆任务，焦虑相关的措施，在明暗箱中测定的母亲删除，但不是父亲删除小鼠的显着损害。新生儿的超声波发声（USV）记录显示，母体缺失幼仔比野生型同窝仔发出更多的USV。在母体缺失小鼠中增加的USV表明母亲和幼崽之间的异常信号传导行为可能反映了人类AS患者的异常交流行为。因此，具有从Ube 3a到Gabrb 3的母体缺失的突变小鼠提供了AS小鼠模型，其在分子上比仅具有Ube 3a突变的小鼠更类似于人类中AS的连续基因缺失形式。这些小鼠将是有价值的，为未来的比较研究，小鼠与母亲缺乏Ube 3a单独。
Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11–q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11–q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m−/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m−/p+), but not paternal (m+/p−), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.
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影响因子：
9.2
作者：
Groszer, Matthias;Keays, David A.;Deacon, Robert M. J.;de Bono, Joseph P.;Prasad-Mulcare, Shweta;Gaub, Simone;Baum, Muriel G.;French, Catherine A.;Nicod, Jrme;Coventry, Julie A.;Enard, Wolfgang;Fray, Martin;Brown, Steve D. M.;Nolan, Patrick M.;Paeaebo, Svante;Channon, Keith M.;Costa, Rui M.;Eilers, Jens;Ehret, Guenter;Nicholas, J.;Rawlins, P.;Fisher, Simon E.
通讯作者：
Fisher, Simon E.
影响因子：
2.6
作者：
Hahn, ME;Schanz, N
通讯作者：
Schanz, N
影响因子：
3.5
作者：
Kashiwagi, A;Meguro, M;Oshimura, M
通讯作者：
Oshimura, M
影响因子：
4.4
作者：
Jiang YH;Wauki K;Liu Q;Bressler J;Pan Y;Kashork CD;Shaffer LG;Beaudet AL
通讯作者：
Beaudet AL
影响因子：
3.5
作者：
Bi, Weimin;Yan, Jiong;Lupski, James R.
通讯作者：
Lupski, James R.