Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, United States of America.
Honors College, Florida Atlantic University, Jupiter, Florida, United States of America.
PLoS Genet. 2020 Jul 22;16(7):e1008920. doi: 10.1371/journal.pgen.1008920. eCollection 2020 Jul.
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 alterations. Thus, global developmental alterations in brain circuits/systems function may contribute to behavioral phenotypes in neurofibromatosis type 1.
神经纤维瘤病 1 型是一种单基因疾病，使个体易患肿瘤形成和认知及行为症状。这些神经症状的神经元回路和发育事件尚不清楚。为了更好地了解潜在基因 (NF1) 的突变如何导致行为改变，我们检查了果蝇神经纤维瘤病 1 模型中的梳理行为。果蝇 NF1 同源物的突变会导致过度梳理，并且在发育过程中敲低 Nf1 时，成年果蝇中观察到梳理增加。此外，需要完整的 Nf1 Ras GAP 相关结构域信号来维持正常的梳理行为。对 Nf1 的需求分布在神经元回路中，当它们平行靶向时会累加，而不是映射到离散的微电路。总的来说，这些数据表明，发育过程中神经元功能的广泛改变，需要完整的 Ras 信号，会导致关键的 NF1 介导的行为改变。因此，大脑回路/系统功能的全局发育改变可能导致神经纤维瘤病 1 型的行为表型。
