Drosophila S6 Kinase like inhibits neuromuscular junction growth by downregulating the BMP receptor thickveins.
Synaptic connections must be precisely controlled to ensure proper neural circuit formation. In Drosophila melanogaster, bone morphogenetic protein (BMP) promotes growth of the neuromuscular junction (NMJ) by binding and activating the BMP ligand receptors wishful thinking (Wit) and thickveins (Tkv) expressed in motor neurons. We report here that an evolutionally conserved, previously uncharacterized member of the S6 kinase (S6K) family S6K like (S6KL) acts as a negative regulator of BMP signaling. S6KL null mutants were viable and fertile but exhibited more satellite boutons, fewer and larger synaptic vesicles, larger spontaneous miniature excitatory junctional potential (mEJP) amplitudes, and reduced synaptic endocytosis at the NMJ terminals. Reducing the gene dose by half of tkv in S6KL mutant background reversed the NMJ overgrowth phenotype. The NMJ phenotypes of S6KL mutants were accompanied by an elevated level of Tkv protein and phosphorylated Mad, an effector of the BMP signaling pathway, in the nervous system. In addition, Tkv physically interacted with S6KL in cultured S2 cells. Furthermore, knockdown of S6KL enhanced Tkv expression, while S6KL overexpression downregulated Tkv in cultured S2 cells. This latter effect was blocked by the proteasome inhibitor MG132. Our results together demonstrate for the first time that S6KL regulates synaptic development and function by facilitating proteasomal degradation of the BMP receptor Tkv.
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Guoli
G
Zhao
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Yingga
Y
Wu
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China; College of Life Science, Hubei University, Wuhan, China.
Li
L
Du
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Wenhua
W
Li
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Ying
Y
Xiong
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Aiyu
A
Yao
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Qifu
Q
Wang
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Beijing, China.
Yong Q
YQ
Zhang
D000818:Animals; D030801:Animals, Genetically Modified; D052004:Bone Morphogenetic Protein Receptors / Q000096:biosynthesis* / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development; D004705:Endocytosis / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism; D009469:Neuromuscular Junction / Q000254:growth & development* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics
D019485:Bone Morphogenetic Proteins; D029721:Drosophila Proteins; D011956:Receptors, Cell Surface; C090169:tkv protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D052004:Bone Morphogenetic Protein Receptors