Abstract
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.
Highlights
Reliable and effective communication between neurons and their targets across the synaptic cleft through cell adhesion molecules and signaling pathways is critical for the formation, growth, and plasticity of synapses [1,2,3]
Bone morphogenetic protein (BMP) acts as a retrograde signal promoting synaptic growth at the Drosophila neuromuscular junction (NMJ), but little is known about proteins that regulate bone morphogenetic protein (BMP) signaling by controlling BMP release, receptor expression, and signal transduction
S6K like (S6KL) Inhibits BMP Signaling at NMJ Synapses
Summary
Reliable and effective communication between neurons and their targets across the synaptic cleft through cell adhesion molecules and signaling pathways is critical for the formation, growth, and plasticity of synapses [1,2,3]. The retrograde bone morphogenetic protein (BMP) signaling from postsynaptic muscles to presynaptic motoneurons is crucial for synaptic development and plasticity at the Drosophila larval neuromuscular junctions (NMJs) [4,5,6,7,8]. At the Drosophila NMJ, the BMP homolog Glass bottom boat (Gbb) is secreted from muscles and binds to the constitutively active presynaptic BMP type II receptor wishful thinking (Wit), which in turn leads to the recruitment of the type I receptors thickveins (Tkv) and saxophone (Sax). Phosphorylated Mad (pMad) forms a complex with co-Smad Medea that translocates to the nucleus and regulates the transcription of target genes required for NMJ growth. BMP pathway is both required and sufficient for Drosophila NMJ growth
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