title: Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila.
abstract: Altered expression of the E3 ubiquitin ligase UBE3A, which is involved in protein degradation through the proteasome-mediated pathway, is associated with neurodevelopmental and behavioral defects observed in Angelman syndrome (AS) and autism. However, little is known about the neuronal function of UBE3A and the pathogenesis of UBE3A-associated disorders. To understand the in vivo function of UBE3A in the nervous system, we generated multiple mutations of ube3a, the Drosophila ortholog of UBE3A. We found a significantly increased number of total boutons and satellite boutons in conjunction with compromised endocytosis in the neuromuscular junctions (NMJs) of ube3a mutants compared to the wild type. Genetic and biochemical analysis showed upregulation of bone morphogenetic protein (BMP) signaling in the nervous system of ube3a mutants. An immunochemical study revealed a specific increase in the protein level of Thickveins (Tkv), a type I BMP receptor, but not other BMP receptors Wishful thinking (Wit) and Saxophone (Sax), in ube3a mutants. Ube3a was associated with and specifically ubiquitinated lysine 227 within the cytoplasmic tail of Tkv, and promoted its proteasomal degradation in Schneider 2 cells. Negative regulation of Tkv by Ube3a was conserved in mammalian cells. These results reveal a critical role for Ube3a in regulating NMJ synapse development by repressing BMP signaling. This study sheds new light onto the neuronal functions of UBE3A and provides novel perspectives for understanding the pathogenesis of UBE3A-associated disorders.
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Aiyu
authors.initials: A
authors.lastname: Yao
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Hui
authors.identifier: 0000-0001-9708-7998
authors.initials: H
authors.lastname: Zhi
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Kuldeep
authors.initials: K
authors.lastname: Kaur
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yong-Chuan
authors.initials: YC
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Mingyue
authors.identifier: 0000-0003-1291-1111
authors.initials: M
authors.lastname: Jia
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Qifu
authors.initials: Q
authors.lastname: Wang
authors.affiliation: College of Life Science, Hubei University, Wuhan, Hubei, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Jin
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Guoli
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics* / Q000473:pathology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics*; D004705:Endocytosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D009469:Neuromuscular Junction / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D013569:Synapses / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D019485:Bone Morphogenetic Proteins; D029721:Drosophila Proteins; D011956:Receptors, Cell Surface; C449821:wit protein, Drosophila; C532444:Ube3a protein, Drosophila; D044767:Ubiquitin-Protein Ligases; C090169:tkv protein, Drosophila; D017346:Protein Serine-Threonine Kinases