Tao Negatively Regulates BMP Signaling During Neuromuscular Junction Development in Drosophila

Abstract

The coordinated growth and development of synapses is critical for all aspects of neural circuit function and mutations that disrupt these processes can result in various neurological defects. Several anterograde and retrograde signaling pathways, including the canonical Bone Morphogenic Protein (BMP) pathway, regulate synaptic development in vertebrates and invertebrates. At the Drosophila larval neuromuscular junction (NMJ), the retrograde BMP pathway is a part of the machinery that controls NMJ expansion concurrent with larval growth. We sought to determine whether the conserved Hippo pathway, critical for proportional growth in other tissues, also functions in NMJ development. We found that neuronal loss of the serine‐threonine protein kinase Tao, a regulator of the Hippo signaling pathway, results in supernumerary boutons which contain a normal density of active zones. Tao is also required for proper synaptic function, as reduction of Tao results in NMJs with decreased evoked excitatory junctional potentials. Surprisingly, Tao function in NMJ growth is independent of the Hippo pathway. Instead, our experiments suggest that Tao negatively regulates BMP signaling as reduction of Tao leads to an increase in pMad levels in motor neuron nuclei and an increase in BMP target gene expression. Taken together, these results support a role for Tao as a novel inhibitor of BMP signaling in motor neurons during synaptic development and function.

Neuronal Hippo signaling: From development to diseases

“…A recent study has shown that a regulator of the Hippo signaling pathway, Tao kinase, is essential for proper synaptic function in NMJ of Drosophila . Surprisingly, Tao functions in regulating appropriate amount of synaptic bouton formation by negatively regulating BMP signaling and in a Hippo signaling independent manner (Politano et al., 2019).…”

Target‐dependent retrograde signaling mediates synaptic plasticity at the Drosophila neuromuscular junction

“…Synaptic pMad is likely part of a complex system involving receptor dynamics and endosomal processing/shuttling, that ‘tags’ axonal branches for growth, maturation, and plasticity. The molecular mechanisms known to regulate local BMP signaling in presynaptic boutons are diverse: the dynamics of nuclear importins, interactions with other trans‐synaptic and cytoplasmic signaling systems, recycling of BMP receptors through endocytic and endosomal regulation, RNA binding protein activity, phospholipid composition, and cytoskeletal regulation (Banerjee & Riordan, ; Banerjee, Venkatesan, & Bhat, ; Deshpande et al, ; Eaton & Davis, ; Fuentes‐Medel et al, ; Heo et al, ; Higashi‐Kovtun et al, ; Huang et al, ; Kim et al, ; Li et al, ; Liu et al, ; Merino et al, ; Piccioli & Littleton, ; Politano et al, ; Sulkowski et al, ; Summerville et al, ; Vanlandingham et al, ; Zhang et al, ; Zhao et al, ). Local, retrograde effects are also possible through muscle‐specific regulation of glutamate receptor composition and Gbb production/release (this study; also see Halstead et al, ; Sulkowski et al, ).…”

Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

“…Using Drosophila (neuron-muscle junction) NMJ as a classic system for studying synaptic development (Broadie and Bate, 1995 ; Menon et al, 2013 ; Frank, 2014 ) assists neurobiologist in identifying multiple psychiatric disorder related genes and their underlying molecular mechanisms (Sun and Xie, 2012 ; Tian et al, 2017 ). Knockdown or deactivation (hypomorphic allele) of Drosophila Tao increases the number of NMJ (buttons, the single NMJ structure; Politano et al, 2019 ). However, it seems Drosophila Tao that regulates NMJ development is not dependent on the Hippo/MST pathway as it is in hippocampal neurons (Ultanir et al, 2014 ) but it could negatively regulate BMP signaling as reduction of Drosophila Tao leads to an increase in both nucleic pMad levels and BMP target gene expression in motor neuron (Politano et al, 2019 ).…”

“…Knockdown or deactivation (hypomorphic allele) of Drosophila Tao increases the number of NMJ (buttons, the single NMJ structure; Politano et al, 2019 ). However, it seems Drosophila Tao that regulates NMJ development is not dependent on the Hippo/MST pathway as it is in hippocampal neurons (Ultanir et al, 2014 ) but it could negatively regulate BMP signaling as reduction of Drosophila Tao leads to an increase in both nucleic pMad levels and BMP target gene expression in motor neuron (Politano et al, 2019 ). However, another study recently showed that knockdown of Tao could decrease the NMJ number (Dulovic-Mahlow et al, 2019 ).…”