Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra syndrome.
Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra syndrome.
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在克莱夫斯特拉综合征小鼠模型中，炎症相关基因的去抑制与小胶质细胞激活和神经成熟缺陷有关。
DOI：
10.1016/j.isci.2021.102741
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发表时间：
2021-07-23
期刊：
影响因子：
5.8
通讯作者：
Shinkai Y
中科院分区：
文献类型：
--
作者：
Yamada A;Hirasawa T;Nishimura K;Shimura C;Kogo N;Fukuda K;Kato M;Yokomori M;Hayashi T;Umeda M;Yoshimura M;Iwakura Y;Nikaido I;Itohara S;Shinkai Y
编码组蛋白H3赖氨酸9（H3 K9）甲基转移酶G9 a样蛋白（GLP）的EHMT 1单倍不足导致Kleefstra综合征（KS），一种发育迟缓和智力残疾的复杂疾病。在这里，我们检查了出生后供应GLP是否可以逆转作为KS模型的Ehmt 1 Δ/+小鼠中观察到的神经表型。从幼年期开始的普遍GLP供应改善了Ehmt 1 Δ/+小鼠的行为异常。出生后神经元特异性GLP供应不足以改善Ehmt 1 Δ/+小鼠的异常行为，但仍逆转了H3 K9 me 2和脊柱数量的减少。有趣的是，一些炎症基因，包括IL-1β（Il 1b），在Ehmt 1 Δ/+脑中上调和激活的小胶质细胞增加，并且这些表型也被神经元特异性出生后GLP供应逆转。Il 1b失活消除了Ehmt 1 Δ/+小鼠中的小胶质细胞和棘数目表型。因此，H3 K9 me 2和一些神经学表型是可逆的，但行为异常更难以改善，这取决于GLP供应的时间。Kleefstra综合征Ehmt 1 Δ/+小鼠模型中激活的小胶质细胞增加出生后GLP供应可逆转Ehmt 1 Δ/+小鼠神经元中H3 K9 me 2的减少幼年阶段的GLP供应可改善Ehmt 1 Δ/+小鼠的异常行为Il 1b KO消除Ehmt 1 Δ/+小鼠中的小胶质细胞和脊柱数量表型病理生理学;行为神经科学;分子神经科学;发育神经科学
Haploinsufficiency of EHMT1, which encodes histone H3 lysine 9 (H3K9) methyltransferase G9a-like protein (GLP), causes Kleefstra syndrome (KS), a complex disorder of developmental delay and intellectual disability. Here, we examined whether postnatal supply of GLP can reverse the neurological phenotypes seen in Ehmt1Δ/+ mice as a KS model. Ubiquitous GLP supply from the juvenile stage ameliorated behavioral abnormalities in Ehmt1Δ/+ mice. Postnatal neuron-specific GLP supply was not sufficient for the improvement of abnormal behaviors but still reversed the reduction of H3K9me2 and spine number in Ehmt1Δ/+ mice. Interestingly, some inflammatory genes, including IL-1β (Il1b), were upregulated and activated microglial cells increased in the Ehmt1Δ/+ brain, and such phenotypes were also reversed by neuron-specific postnatal GLP supply. Il1b inactivation canceled the microglial and spine number phenotypes in the Ehmt1Δ/+ mice. Thus, H3K9me2 and some neurological phenotypes are reversible, but behavioral abnormalities are more difficult to improve depending on the timing of GLP supply. Activated microglias increase in a Ehmt1Δ/+ mouse model of Kleefstra syndrome Diminished H3K9me2 in Ehmt1Δ/+ mouse neurons is reversed by post-natal GLP supply GLP supply from the juvenile stage can improve abnormal behaviors of Ehmt1Δ/+ mice Il1b KO cancelles the microglial and spine number phenotypes in the Ehmt1Δ/+ mice Pathophysiology; Behavioral neuroscience; Molecular neuroscience; Developmental neuroscience
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影响因子：
16.6
作者：
Hayashi T;Ozaki H;Sasagawa Y;Umeda M;Danno H;Nikaido I
通讯作者：
Nikaido I
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
32.4
作者：
Cronk JC;Derecki NC;Ji E;Xu Y;Lampano AE;Smirnov I;Baker W;Norris GT;Marin I;Coddington N;Wolf Y;Turner SD;Aderem A;Klibanov AL;Harris TH;Jung S;Litvak V;Kipnis J
通讯作者：
Kipnis J
影响因子：
7
作者：
Fukuda K;Okuda A;Yusa K;Shinkai Y
通讯作者：
Shinkai Y
影响因子：
9.8
作者：
Kleefstra, Tjitske;Brunner, Han G.;van Bokhoven, Hans
通讯作者：
van Bokhoven, Hans