Brunskill Eric W, Ehrman Lisa A, Williams Michael T, Klanke Justin, Hammer Daniel, Schaefer Tori L, Sah Renu, Dorn Gerald W, Potter S Steven, Vorhees Charles V
Division of Cardiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
Eur J Neurosci. 2005 Sep;22(6):1265-76. doi: 10.1111/j.1460-9568.2005.04291.x.
Npas3 is a member of the bHLH-PAS superfamily of transcription factors that is expressed broadly in the developing neuroepithelium. To study the function of this gene, mice deficient in Npas3 were generated and characterized. Npas3-/- mice were growth-retarded and exhibited developmental brain abnormalities that included a reduction in size of the anterior hippocampus, hypoplasia of the corpus callosum and enlargement of the ventricles. A number of behavioural abnormalities were identified in Npas3-/- mice including locomotor hyperactivity, subtle gait defects, impairment of prepulse inhibition of acoustic startle, deficit in recognition memory and altered anxiety-related responses. Characterization of neurosignaling pathways using several pharmacological agents revealed dysfunctional glutamate, dopamine and serotonin neurotransmitter signaling. Consistent with these findings, we identified a significant alteration in cortical PSD-95 expression, a PDZ-containing protein that has been shown to be involved in postsynaptic signal transduction. Together, our observations indicate an important role for Npas3 in controlling normal brain development and neurosignaling pathways.
Npas3是转录因子bHLH-PAS超家族的成员，在发育中的神经上皮广泛表达。为了研究该基因的功能，我们构建并鉴定了Npas3基因缺陷小鼠。Npas3基因敲除小鼠生长发育迟缓，并表现出发育性脑异常，包括前海马体体积减小、胼胝体发育不全和脑室扩大。在Npas3基因敲除小鼠中发现了许多行为异常，包括运动活动亢进、轻微步态缺陷、听觉惊吓前脉冲抑制受损、识别记忆缺陷以及焦虑相关反应改变。使用几种药物对神经信号通路进行表征，发现谷氨酸、多巴胺和5-羟色胺神经递质信号功能失调。与这些发现一致，我们发现皮质PSD-95表达有显著改变，PSD-95是一种含PDZ的蛋白质，已被证明参与突触后信号转导。总之，我们的观察结果表明Npas3在控制正常脑发育和神经信号通路中起重要作用。
