Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis.
Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis.
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DOI：
10.1038/mp.2017.158
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发表时间：
2018-04
影响因子：
11
通讯作者：
Hiroi N
中科院分区：
文献类型：
--
作者：
Boku S;Izumi T;Abe S;Takahashi T;Nishi A;Nomaru H;Naka Y;Kang G;Nagashima M;Hishimoto A;Enomoto S;Duran-Torres G;Tanigaki K;Zhang J;Ye K;Kato S;Männistö PT;Kobayashi K;Hiroi N
工作记忆能力是执行功能的一个重要组成部分，从童年到成年都在发展。在自闭症谱系障碍（ASD），精神分裂症和智力残疾（ID）的个体中可以看到这种发育过程的异常，这表明这种非典型过程与发育性神经精神障碍的轨迹有关。然而，这一过程背后的细胞和神经元底物尚不清楚。22q11.2拷贝数变异体的重复和三倍始终与人类ASD和ID的认知缺陷相关，并且小22q11.2片段的过表达概括了小鼠发育性神经精神障碍的维度方面。我们利用这两条线索来深入研究工作记忆非典型发育的细胞基质。使用区域和细胞类型选择性的基因表达方法，我们证明了儿茶酚-O-甲基转移酶（COMT）或Tbx 1，两个基因编码的两个小22q11.2节段，在成年神经干/祖细胞在海马中的拷贝数升高，防止小鼠的工作记忆能力的发育成熟。此外，COMT或Tbx 1的拷贝数升高降低了成年神经干/祖细胞在体外以细胞自主方式增殖，并降低了其后代在体内海马颗粒层中的迁移。我们的数据提供了新的假设，这些22q11.2基因的拷贝数升高改变工作记忆能力的发展轨迹，通过次优的成年海马神经发生的证据。
Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.
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影响因子：
6.9
作者：
David, AS;Malmberg, A;Lewis, G
通讯作者：
Lewis, G
影响因子：
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作者：
Barnett, Jennifer H.;Scoriels, Linda;Munafo, Marcus R.
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作者：
Dennis CV;Suh LS;Rodriguez ML;Kril JJ;Sutherland GT
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影响因子：
23.9
作者：
Encinas, Juan M.;Michurina, Tatyana V.;Peunova, Natalia;Park, June-Hee;Tordo, Julie;Peterson, Daniel A.;Fishell, Gord;Koulakov, Alex;Enikolopov, Grigori
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Enikolopov, Grigori
影响因子：
3.1
作者：
Danielsson, Henrik;Henry, Lucy;Nilsson, Lars-Goran
通讯作者：
Nilsson, Lars-Goran