Role of the STRIPAK complex and the Hippo pathway in synaptic terminal formation

To transmit neural information from pre to postsynaptic neurons, the number, morphology, and function of the synapse have to be strictly regulated. Failures in synaptic formations are linked to neural disorders. For example, it is suggested that localization of N-methyl-D-aspartate (NMDA) receptors plays important roles in NMDA receptor-induced excitotoxicity, which is in turn thought to contribute to cell death associated with certain neurodegenerative diseases (Parsons and Raymond, 2014). Furthermore, synaptic overgrowth is observed in Drosophila dfmr1 (homolog of mammalian FMR1) gene mutant, which causes the Fragile X syndrome (Zhang et al., 2001). In this perspective, we introduce the involvement of the striatin-interacting phosphatase and kinase (STRIPAK) complex in synapse formation. Recent proteomic studies have identified the evolutionarily conserved STRIPAK complex that regulates various cellular processes including cell-cycle control and cell polarity (Figure 1A; Hwang and Pallas, 2014). The main component of STRIPAK complex is striatin, which belongs to the subfamily of regulatory B subunits of the protein phosphatase 2A (PP2A) complex. The A and C subunits of PP2A complex, CCM3, Mob3, Mst3, Mst4, Ysk1, Ccm3, Strip1, and Strip2 form the core mammalian STRIPAK complex together with striatin. This multi-component core complex is capable of assembling in a mutually exclusive manner with other accessory proteins depending on the function that it mediates (Hwang and Pallas, 2014). Although the role of STRIPAK complexes in cellular processes of multiple organisms has been extensively studied in recent years, little is known about the role of STRIPAK complex in synapse formation. Thus, while it was reported that the Drosophila mutant of Mob4 (homolog of mammalian Mob3) shows abnormal synaptic terminal development (Hwang and Pallas, 2014), no information is available regarding the underlying mechanism. We have previously identified that Drosophila Strip (homolog of mammalian Strip1 and 2) is expressed at the synaptic sites and regulates axon elongation and dendrite branching in olfactory projection neurons (Sakuma et al., 2014). Since Drosophila larval neuromuscular junction (NMJ) is the established model to study synapse formation, we examined the localization of Strip at larval NMJ and found that Strip showed a punctate distribution at the presynaptic sites (Sakuma et al., 2016). Drosophila NMJs are composed of chains of oval structures called boutons that contain multiple active zones (which serve as neurotransmitter release sites) (Figure 1B) (Menon et al., 2013). When Strip was knocked down specifically in the presynaptic motor neurons, the number of satellite boutons (small boutons that emanate from the normal boutons and are thought to arise from defects in synaptic growth), was increased (Figure 1C). Hence, we concluded that presynaptic Strip regulates bouton formation. Furthermore, we found that Strip not only regulates synapse formation but also affects synaptic function. This was indicated in our observation that the frequency of miniature excitatory junction potential was increased when Strip was knocked down in the presynaptic motor neurons. To clarify the role of Strip in synapse formation, we focused on the Hippo pathway, which is known to be a major regulator of cell proliferation and cell death (Staley and Irvine, 2012). The Hippo pathway was investigated because a previous report suggested that the Drosophila STRIPAK complex serves as a negative regulator of Hippo (Ribeiro et al., 2010). Using Dro-