title: dAcsl, the Drosophila ortholog of acyl-CoA synthetase long-chain family member 3 and 4, inhibits synapse growth by attenuating bone morphogenetic protein signaling via endocytic recycling.
abstract: Fatty acid metabolism plays an important role in brain development and function. Mutations in acyl-CoA synthetase long-chain family member 4 (ACSL4), which converts long-chain fatty acids to acyl-CoAs, result in nonsyndromic X-linked mental retardation. ACSL4 is highly expressed in the hippocampus, a structure critical for learning and memory. However, the underlying mechanism by which mutations of ACSL4 lead to mental retardation remains poorly understood. We report here that dAcsl, the Drosophila ortholog of ACSL4 and ACSL3, inhibits synaptic growth by attenuating BMP signaling, a major growth-promoting pathway at neuromuscular junction (NMJ) synapses. Specifically, dAcsl mutants exhibited NMJ overgrowth that was suppressed by reducing the doses of the BMP pathway components, accompanied by increased levels of activated BMP receptor Thickveins (Tkv) and phosphorylated mothers against decapentaplegic (Mad), the effector of the BMP signaling at NMJ terminals. In addition, Rab11, a small GTPase involved in endosomal recycling, was mislocalized in dAcsl mutant NMJs, and the membrane association of Rab11 was reduced in dAcsl mutant brains. Consistently, the BMP receptor Tkv accumulated in early endosomes but reduced in recycling endosomes in dAcsl mutant NMJs. dAcsl was also required for the recycling of photoreceptor rhodopsin in the eyes, implying a general role for dAcsl in regulating endocytic recycling of membrane receptors. Importantly, expression of human ACSL4 rescued the endocytic trafficking and NMJ phenotypes of dAcsl mutants. Together, our results reveal a novel mechanism whereby dAcsl facilitates Rab11-dependent receptor recycling and provide insights into the pathogenesis of ACSL4-related mental retardation.
authors.affiliation: Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, and Institute of Life Science and the Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.forename: Sheng
authors.initials: S
authors.lastname: Huang
authors.forename: Qifu
authors.initials: Q
authors.lastname: Wang
authors.forename: Junhai
authors.initials: J
authors.lastname: Han
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000187:drug effects / Q000502:physiology*; D003066:Coenzyme A Ligases / Q000494:pharmacology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D009132:Muscles / Q000378:metabolism; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017661:Receptors, Presynaptic / Q000187:drug effects; D012243:Rhodopsin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000187:drug effects*; D022161:Transport Vesicles / Q000187:drug effects*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D000099193:rab11 GTP-Binding Proteins
chemical_list: D019485:Bone Morphogenetic Proteins; D003066:Coenzyme A Ligases; D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D017661:Receptors, Presynaptic; D012243:Rhodopsin; D020691:rab GTP-Binding Proteins; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D000099193:rab11 GTP-Binding Proteins; C090169:tkv protein, Drosophila
keywords: BMP signaling; Drosophila; mental retardation; neuromuscular junction; synapse; vesicle trafficking