Liprin-α is required for photoreceptor target selection in Drosophila

Abstract

Classical cadherin-mediated interactions between axons and dendrites are critical to target selection and synapse assembly. However, the molecular mechanisms by which these interactions are controlled are incompletely understood. In the Drosophila visual system, N-cadherin is required in both photoreceptor (R cell) axons and their targets to mediate stabilizing interactions required for R cell target selection. Here we identify the scaffolding protein Liprin-␣ as a critical component in this process. We isolated mutations in Liprin-␣ in a genetic screen for mutations affecting the pattern of synaptic connections made by R1-R6 photoreceptors. Using eye-specific mosaics, we demonstrate a previously undescribed, axonal function for Liprin-␣ in target selection: Liprin-␣ is required to be cell-autonomous in all subtypes of R1-R6 cells for their axons to reach their targets. Because Liprin-␣, the receptor tyrosine phosphatase LAR, and N-cadherin share qualitatively similar mutant phenotypes in R1-R6 cells and are coexpressed in R cells and their synaptic targets, we infer that these three genes act at the same step in the targeting process. However, unlike Ncadherin, neither Liprin-␣ nor LAR is required postsynaptically for R cells to project to their correct targets. Thus, these two proteins, unlike N-cadherin, are functionally asymmetric between axons and dendrites. We propose that the adhesive mechanisms that link preand postsynaptic cells before synapse formation may be differentially regulated in these two compartments.axon ͉ synapse formation ͉ cadherin ͉ cell adhesion

Investigating CNS synaptogenesis at single-synapse resolution by combining reverse genetics with correlative light and electron microscopy

“…Liprin-α interacts with Leukocyte-antigen-related-like (Lar) and DSyd-1 (RhoGAP100F), and overlapping but non-identical phenotypes have been described upon disruption of these genes in Drosophila (Choe et al, 2006;Hofmeyer et al, 2006;Holbrook et al, 2012;Kaufmann et al, 2002). Consistent with a potential shared role of these three factors in synapse assembly, we found In the magnification, the approximate region in which mitochondria were scored in O-R is indicated in yellow.…”

“…Liprin-α acts as an important synapse organizer in both vertebrates and invertebrates (Spangler and Hoogenraad, 2007). In Drosophila, Liprin-α is also required for post-synaptic target selection in photoreceptors, but not at the NMJ (Choe et al, 2006;Hofmeyer et al, 2006;Kaufmann et al, 2002). Loss of Liprin-α did not alter ms axon branching or branch targeting, but led to a pronounced decrease of Syt1 marker along axon branches and an aberrant accumulation of signal at distal tips of axon branches.…”

The receptor protein tyrosine phosphatase LAR promotes R7 photoreceptor axon targeting by a phosphatase-independent signaling mechanism

“…The R7 targeting defect reflects reduced adhesion to target neurons (4,6), while NMJ growth is achieved by sprouting and extension of new axonal branches. The two signaling modes probably require distinct downstream factors, in addition to common components such as Liprin-␣ (3,6,10,34,48). The different requirements for LAR structural motifs make it possible to selectively interfere with only a subset of LARdependent processes.…”

“…We wanted to test its activity on a substrate relevant for LAR function in vivo. The intracellular LARbinding protein Liprin-␣ acts downstream of LAR in NMJ synapse growth and photoreceptor axon targeting, and is tyrosine phosphorylated in S2Rϩ cells (3,10,34). To facilitate the detection of LAR phosphatase activity in S2Rϩ cells, we increased the tyrosine phosphorylation of HA-tagged Liprin-␣ by coexpressing the Abelson (Abl) protein kinase (Fig.…”

The cytoskeletal regulator Genghis khan is required for columnar target specificity in theDrosophilavisual system

“…For example, the classical cadherin Ncadherin mediates interactions between pre-and post-synaptic cells that are required for the targeting choices made by R1-R6 cells, and by R7 cells (Ting et al, 2005;Prakash et al, 2005;Yonekura et al, 2007). The receptor tyrosine phosphatases Lar and Ptp69D, as well as the Lar-interacting protein Liprin-, stabilize these connections (Newsome et al, 2000a;Clandinin et al, 2001;Maurel-Zaffran et al, 2001;Choe et al, 2006;Hofmeyer et al, 2006;Hofmeyer et al, 2009;Prakash et al, 2009). Dynamic regulation of the expression of N-cadherin and Lar is also crucial to the layer-specific targeting decisions of R7 and R8 (Petrovic and Hummel, 2008).…”