Tischfield David J, Saraswat Dave K, Furash Andrew, Fowler Stephen C, Fuccillo Marc V, Anderson Stewart A
Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA; Department of Psychiatry, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine ARC 517, Philadelphia, PA 19104-5127, USA.
Department of Psychiatry, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine ARC 517, Philadelphia, PA 19104-5127, USA.
Neurobiol Dis. 2017 Jul;103:174-183. doi: 10.1016/j.nbd.2017.04.013. Epub 2017 Apr 19.
The zinc-finger SWIM domain-containing protein 6 (ZSWIM6) is a protein of unknown function that has been associated with schizophrenia and limited educational attainment by three independent genome-wide association studies. Additionally, a putatively causal point mutation in ZSWIM6 has been identified in several cases of acromelic frontonasal dysostosis with severe intellectual disability. Despite the growing number of studies implicating ZSWIM6 as an important regulator of brain development, its role in this process has never been examined. Here, we report the generation of Zswim6 knockout mice and provide a detailed anatomical and behavioral characterization of the resulting phenotype. We show that Zswim6 is initially expressed widely during embryonic brain development but becomes restricted to the striatum postnatally. Loss of Zswim6 causes a reduction in striatal volume and changes in medium spiny neuron morphology. These changes are associated with alterations in motor control, including hyperactivity, impaired rotarod performance, repetitive movements, and behavioral hyperresponsiveness to amphetamine. Together, our results show that Zswim6 is indispensable to normal brain function and support the notion that Zswim6 might serve as an important contributor to the pathogenesis of schizophrenia and other neurodevelopmental disorders.
含锌指SWIM结构域蛋白6（ZSWIM6）是一种功能未知的蛋白质，三项独立的全基因组关联研究将其与精神分裂症和受教育程度有限联系起来。此外，在几例患有严重智力残疾的肢端颜面鼻发育不全病例中，已鉴定出ZSWIM6中一个可能具有因果关系的点突变。尽管越来越多的研究表明ZSWIM6是大脑发育的重要调节因子，但其在这一过程中的作用从未被研究过。在这里，我们报告了Zswim6基因敲除小鼠的产生，并对由此产生的表型进行了详细的解剖学和行为学特征描述。我们发现，Zswim6在胚胎脑发育过程中最初广泛表达，但在出生后局限于纹状体。Zswim6的缺失导致纹状体体积减小和中等棘状神经元形态改变。这些变化与运动控制的改变有关，包括多动、转棒试验表现受损、重复运动以及对苯丙胺的行为反应过度。总之，我们的结果表明，Zswim6对正常脑功能不可或缺，并支持Zswim6可能是精神分裂症和其他神经发育障碍发病机制的重要促成因素这一观点。
