TATA-box结合蛋白相关因子1(TAF1)是一种广泛表达的蛋白,是基础转录因子TFIID的最大亚基,在RNA聚合酶II依赖性转录的启动中起关键作用。男性的TAF1错义变体会导致X连锁智力残疾,神经发育障碍,TAF1在X连锁肌张力障碍-帕金森病中失调,神经退行性疾病.然而,该领域缺乏TAF1疾病的遗传小鼠模型来探索哺乳动物的机制和治疗。这里,我们产生并验证了一个条件cre-lox等位基因,和第一个无处不在的Taf1敲除老鼠。我们发现男性Taf1缺失是胚胎致死的,这可能解释了为什么没有发现人类无效变体。在Taf1杂合雌性的大脑中,在总体结构上没有发现差异,整体表达,和蛋白质定位,表明X失活向非突变染色体极端偏斜。然而,这些雌性小鼠的体重显着增加,体重随年龄增长,减少运动,表明一小部分神经元受到Taf1损失的负面影响。最后,这种新小鼠可能是开发TAF1疾病治疗药物的未来平台.
The TATA box-binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of the basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in human males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked dystonia-parkinsonism, a neurodegenerative disorder. However, this field has lacked a genetic mouse model of TAF1 disease to explore its mechanism in mammals and treatments. Here, we generated and validated a conditional cre-lox allele and the first ubiquitous Taf1 knockout mouse. We discovered that Taf1 deletion in male mice was embryonically lethal, which may explain why no null variants have been identified in humans. In the brains of Taf1 heterozygous female mice, no differences were found in gross structure, overall expression and protein localisation, suggesting extreme skewed X inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting that a small subset of neurons was negatively impacted by Taf1 loss. Finally, this new mouse model may be a future platform for the development of TAF1 disease therapeutics.