Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

Abstract

Precise coordination of synaptic connections ensures proper information flow within circuits. The activity of presynaptic organizing molecules signaling to downstream pathways is essential for such coordination, though such entities remain incompletely known. We show that LRP4, a conserved transmembrane protein known for its postsynaptic roles, functions presynaptically as an organizing molecule. In the Drosophila brain, LRP4 localizes to the nerve terminals at or near active zones. Loss of presynaptic LRP4 reduces excitatory (not inhibitory) synapse number, impairs active zone architecture, and abolishes olfactory attraction - the latter of which can be suppressed by reducing presynaptic GABAB receptors. LRP4 overexpression increases synapse number in excitatory and inhibitory neurons, suggesting an instructive role and a common downstream synapse addition pathway. Mechanistically, LRP4 functions via the conserved kinase SRPK79D to ensure normal synapse number and behavior. This highlights a presynaptic function for LRP4, enabling deeper understanding of how synapse organization is coordinated.DOI: http://dx.doi.org/10.7554/eLife.27347.001

Expansion microscopy of zebrafish for neuroscience and developmental biology studies

“…The proExM protocol has been previously successfully used in a variety of applications and tissue types, including cell culture as well as mouse brain slices ( 2 , 33 ); mouse lung, spleen, and pancreas slices ( 2 ); isolated mouse mitochondria ( 34 ); planaria ( 35 ); the central nervous system and the germarium tip of ovaries in Drosophila ( 36 , 37 ) and human tissue specimens prepared in a variety of different manners ( 32 , 38 ). In many of these tissue types, the isotropy of expansion at the nanoscale was validated by comparison of postexpansion confocal images with superresolution structured-illumination microscopy (SIM) images of the same samples preexpansion [cell culture, mouse brain, and pancreas slices ( 2 ) and human breast biopsy tissue slices ( 32 )].…”

Active Zone Scaffold Protein Ratios Tune Functional Diversity across Brain Synapses

“…The Drosophila system with its unique possibilities for genetic intervention should be an ideal model for studying cellular interactions systematically in the context of establishing synaptic diversity. Cell adhesion proteins, for example, the newly discovered teneurins (Hong et al, 2012; Mosca and Luo, 2014) or LRP4 (Mosca et al, 2017), are attractive candidates for instructing and maintaining AZ diversity via scaffold protein clustering. Interestingly, postsynaptically expressed cell adhesion proteins have been shown to instruct short-term plasticity at hippocampal synapses (Sylwestrak and Ghosh, 2012).…”

The Roles of the Wnt-Antagonists Axin and Lrp4 during Embryogenesis of the Red Flour Beetle Tribolium castaneum

“…In the mouse, LRP4 acts at the neuromuscular junction as a receptor for the motoneuron-derived protein Agrin that is absent from the Drosophila genome [ 45 ]. An Lrp4 ortholog in Drosophila has been identified as a regulator of synaptic physiology in the central nervous system in a Wnt-independent fashion [ 17 ]. The reduction of Lrp4 function in Drosophila results in the loss of certain synapses but has no implications for the segmentation process [ 17 ].…”

“…Consequently, downregulation of Tc-axin resulted in severely affected embryos consisting of posterior abdominal segments only [ 16 ]. The Drosophila Lrp4 ortholog is expressed in the adult brain and functions independently of a Wnt-ligand in synaptogenesis [ 17 ]. Lrp4 in vertebrates can interact with Wnts [ 18 ] and other ligands and has been characterized as a Wnt-modulator in various processes such as the development of skin-appendages [ 19 ], as well as bone [ 20 ] and tooth formation [ 21 ].…”