RRC ID 47657
著者 Li W, Yao A, Zhi H, Kaur K, Zhu YC, Jia M, Zhao H, Wang Q, Jin S, Zhao G, Xiong ZQ, Zhang YQ.
タイトル Angelman Syndrome Protein Ube3a Regulates Synaptic Growth and Endocytosis by Inhibiting BMP Signaling in Drosophila.
ジャーナル PLoS Genet
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.
巻・号 12(5)
ページ e1006062
公開日 2016-5-1
DOI 10.1371/journal.pgen.1006062
PII PGENETICS-D-15-02146
PMID 27232889
PMC PMC4883773
MeSH Angelman Syndrome / genetics* Angelman Syndrome / pathology Animals Bone Morphogenetic Proteins / biosynthesis Bone Morphogenetic Proteins / genetics Disease Models, Animal Drosophila / genetics Drosophila Proteins / biosynthesis* Drosophila Proteins / genetics* Endocytosis / genetics Gene Expression Regulation / genetics Humans Neuromuscular Junction / genetics Neuromuscular Junction / pathology Neurons / metabolism* Neurons / pathology Protein Serine-Threonine Kinases / biosynthesis* Protein Serine-Threonine Kinases / genetics Receptors, Cell Surface / biosynthesis* Receptors, Cell Surface / genetics Signal Transduction Synapses / genetics Ubiquitin-Protein Ligases / biosynthesis Ubiquitin-Protein Ligases / genetics*
IF 5.175
引用数 25
WOS 分野 GENETICS & HEREDITY
リソース情報
ショウジョウバエ DGRC#115298