Affiliations: 1) John Carroll University, Cleveland, OH; 2) Columbia University, New York City, NY
Keywords: f. neuromuscular junction; c. TGFbeta
The canonical Bone Morphogenic Protein (BMP) pathway helps coordinate the growth and development of synapses in both vertebrates and invertebrates. The Drosophila melanogaster neuromuscular junction (NMJ) is a glutamatergic synapse used as a model for the AMPA-type excitatory synapses of the mammalian central nervous system, which develop in a structurally similar way. Retrograde BMP signaling from postsynaptic muscle to presynaptic neuron is critical for the scaling growth of the synaptic termini proportional to larval muscle growth. In the absence of any BMP signaling, NMJs severely undergrow and do not release neurotransmitter normally.
Though nearly twenty years have passed since the identification of the core BMP signaling components regulating synaptic growth and function, we still have an incomplete understanding of how the core pathway itself is regulated. We identified Tao, a conserved serine/threonine kinase implicated in autism, as an inhibitor of retrograde BMP signaling during the scaling growth of the larval NMJ. Loss of neuronal Tao results in overgrowth of synaptic termini without affecting muscle size, suggesting that Tao normally inhibits NMJ growth. Evoked release of neurotransmitter is also impaired in Tao loss-of-function, resulting in larval locomotion defects. Previous studies showed that Tao inhibits growth of epithelial tissues via activation of the conserved Hippo pathway, as a kinase functioning upstream of Hippo itself. In NMJ development, however, Taofunctions independently of Hippo signaling, instead inhibiting the transcription of BMP target genes through a yet-unknown mechanism. We will present our recent progress made in identifying Tao’s neuronal signaling partners and understanding the mechanism by which Tao and its partners inhibit BMP signaling during synapse development.