Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry.
Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry.
复制标题
DOI：
10.1159/000453266
复制
发表时间：
2017-02-01
期刊：
影响因子：
--
通讯作者：
Cheyette, Benjamin N R
中科院分区：
文献类型：
--
作者：
Mulligan, Kimberly A;Cheyette, Benjamin N R
越来越多的证据表明，Wnt信号与包括精神分裂症、双相情感障碍和自闭症谱系障碍在内的多种精神疾病的病理生理学相关。自Wnt配体首次被描述以来的35年里，动物研究已经丰富地探索了下游Wnt信号通路如何影响一系列神经发育过程，以及它们的破坏如何导致神经和行为表型。最近，人类诱导多能干细胞（hiPSC）模型已经开始有助于这方面的文献，同时推动它在越来越多的翻译方向。同时，大规模的人类基因组研究提供的证据表明，Wnt信号通路基因的序列变异有助于在几种精神疾病的发病机制。本文综述了Wnt信号的神经发育和神经发育后功能，强调其破坏可能导致精神疾病的机制，然后回顾了最近最可靠的遗传学证据，支持Wnt通路基因突变导致精神疾病。我们是这样一种观点的支持者，即在动物和hiPSC模型中进行的研究，结合人类遗传数据以及过去几十年基础神经发育研究产生的深层知识库和工具包，将在神经精神病学方面产生近期的切实进展。
Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.