title: Neurofibromin mediates FAK signaling in confining synapse growth at Drosophila neuromuscular junctions.
abstract: Neurofibromatosis type I (NF1), caused by the mutation in the NF1 gene, is characterized by multiple pathological symptoms. Importantly, ~50% of NF1 patients also suffer learning difficulty. Although downstream pathways are well studied, regulation of the NF1-encoded neurofibromin protein is less clear. Here, we focused on the pathophysiology of Drosophila NF1 mutants in synaptic growth at neuromuscular junctions. Our analysis suggests that the Drosophila neurofibromin protein NF1 is required to constrain synaptic growth and transmission. NF1 functions downstream of the Drosophila focal adhesion kinase (FAK) Fak56 and physically interacts with Fak56. The N-terminal region of NF1 mediates the interaction with Fak56 and is required for the signaling activity and presynaptic localization of NF1. In presynapses, NF1 acts via the cAMP pathway, but independent of its GAP activity, to restrain synaptic growth. Thus, presynaptic FAK signaling may be disrupted, causing abnormal synaptic growth and transmission in the NF1 genetic disorder.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Pei-I
authors.initials: PI
authors.lastname: Tsai
authors.forename: Manyu
authors.initials: M
authors.lastname: Wang
authors.forename: Hsiu-Hua
authors.initials: HH
authors.lastname: Kao
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Cheng
authors.forename: James A
authors.initials: JA
authors.lastname: Walker
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
authors.forename: Cheng-Ting
authors.initials: CT
authors.lastname: Chien
mesh_terms: D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000502:physiology*; D055724:Electrophysiological Phenomena / Q000502:physiology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007814:Larva; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009469:Neuromuscular Junction / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D020703:ras GTPase-Activating Proteins / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; C105590:NF1 protein, Drosophila; D009419:Nerve Tissue Proteins; D017661:Receptors, Presynaptic; D020703:ras GTPase-Activating Proteins; D000242:Cyclic AMP; C496049:Fak protein, Drosophila; D051417:Focal Adhesion Kinase 1; D000262:Adenylyl Cyclases