DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling.
DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling.
复制标题
DOI：
10.1038/mp.2016.184
复制
发表时间：
2018-02
影响因子：
11
通讯作者：
Cheyette BNR
中科院分区：
文献类型：
--
作者：
Martin PM;Stanley RE;Ross AP;Freitas AE;Moyer CE;Brumback AC;Iafrati J;Stapornwongkul KS;Dominguez S;Kivimäe S;Mulligan KA;Pirooznia M;McCombie WR;Potash JB;Zandi PP;Purcell SM;Sanders SJ;Zuo Y;Sohal VS;Cheyette BNR
缺乏细胞内Wnt/β-catenin信号通路蛋白DIX domain containing-1（DIXDC 1）的小鼠具有焦虑、抑郁和社会行为的异常测量。这些动物大脑中的锥体神经元减少了树突棘和突触。锂或糖原合成酶激酶-3（GSK 3）抑制剂治疗可纠正这些动物的行为和神经发育表型。对9,000多例自闭症、双相情感障碍和精神分裂症患者的DIXDC 1分析显示，与精神病学未受影响的对照组相比，这些患者中罕见的遗传性序列破坏单核苷酸变异（SNV）的发生率更高。这些SNV中的许多改变了神经主导型DIXDC 1亚型的Wnt/β-连环蛋白信号传导活性;过度激活该途径的一个子集导致显性神经发育效应。我们认为DIXDC 1中罕见的错义SNV通过减少Wnt/β-catenin通路中GSK 3下游的棘和神经元突触密度而导致精神病发病。
Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals’ brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a Glycogen Synthase Kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9,000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single nucleotide variants (SNVs) in these individuals compared to psychiatrically-unaffected controls. Many of these SNVs alter Wnt/β-catenin signaling activity of the neurally-predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/β-catenin pathway.