Abstract：
Neurodevelopmental disorders (NDD) are a group of disorders that include intellectual disability. Although several genes have been implicated in NDD, the molecular mechanisms underlying its pathogenesis remain unclear. Therefore, it is important to develop novel models to analyze the functions of NDD-causing genes in vivo. Recently, rare pathogenic variants of the B-cell lymphoma/leukemia11A/B (BCL11A/B) gene have been identified in several patients with NDD. Drosophila carries the Chronophage (Cph) gene, which has been predicted to be a homolog of BCL11A/B based on the conservation of the amino acid sequence. In the present study, we investigated whether nervous system-specific knockdown of Cph mimics NDD phenotypes in Drosophila. Nervous system-specific knockdown of Cph induced learning and locomotor defects in larvae and epilepsy-like behaviors in adults. The number of synaptic branches was also elevated in the larval neuromuscular junction without a corresponding increase in the number of boutons. Furthermore, the expression levels of putative target genes that are Drosophila homologs of the mammalian BCL11 target genes were decreased in Cph knockdown flies. These results suggest that Cph knockdown flies are a promising model for investigating the pathology of NDD-induced BCL11A/B dysfunction.
摘要：
神经发育障碍（NDD）是一组包括智力障碍的疾病。尽管有几个基因与NDD有关，其发病机制的分子机制尚不清楚.因此,开发新的模型来分析体内NDD致病基因的功能非常重要。最近,已在几名NDD患者中发现了B细胞淋巴瘤/白血病11A/B（BCL11A/B）基因的罕见致病变异。果蝇携带Chronophage(Cph)基因,基于氨基酸序列的保守性,预测其为BCL11A/B的同源物。在本研究中,我们研究了在果蝇中,神经系统特异性敲除Cph是否能模拟NDD表型.cph的神经系统特异性敲除诱导幼虫的学习和运动缺陷以及成人的癫痫样行为。幼虫神经肌肉接头中突触分支的数量也增加了，而boutons的数量却没有相应增加。此外，在Cph击倒果蝇中，哺乳动物BCL11靶基因的果蝇同源的推定靶基因的表达水平降低。这些结果表明，Cph敲低果蝇是研究NDD诱导的BCL11A/B功能障碍病理的有希望的模型。
