Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila

Neurofibromatosis type 1 is a monogenetic disorder that predisposes individuals to tumor formation and cognitive and behavioral symptoms.  The neuronal circuitry and developmental events underlying these neurological symptoms are unknown.  To better understand how mutations of the underlying gene (NF1) drive behavioral alterations, we have examined grooming in the Drosophila neurofibromatosis 1 model.  Mutations of the fly NF1 ortholog drive excessive grooming, and increased grooming was observed in adults when Nf1 was knocked down during development.  Furthermore, intact Nf1 Ras GAP-related domain signaling was required to maintain normal grooming.  The requirement for Nf1 was distributed across neuronal circuits, which were additive when targeted in parallel, rather than mapping to discrete microcircuits.  Overall, these data suggest that broadly-distributed alterations in neuronal function during development, requiring intact Ras signaling, drive key Nf1-mediated behavioral alteratio...

1型神经纤维瘤病（Neurofibromatosis type 1）是一种单基因遗传病，可使个体易罹患肿瘤，并伴随认知与行为异常症状。目前，该疾病相关神经症状背后的神经环路及发育调控机制仍未阐明。为深入探究致病基因NF1的突变如何驱动行为改变，我们以果蝇（Drosophila）1型神经纤维瘤病模型为研究体系，对其理毛行为进行了系统分析。实验结果显示，果蝇NF1同源基因的突变会引发过度理毛行为；若在发育阶段敲低Nf1的表达，成年果蝇也会出现理毛频率升高的表型。进一步研究表明，维持正常理毛行为需要完整的Nf1 Ras GAP相关结构域信号通路。此外，Nf1的功能需求广泛分布于多个神经环路中，并行靶向这些环路时会产生加性效应，而非局限于单一离散微环路。综上，本研究数据提示，发育阶段神经元功能的广泛异常（依赖完整的Ras信号通路）是介导Nf1相关行为改变的核心机制……