Sticks and Stones, a conserved cell surface ligand for the Type IIa RPTP Lar, regulates neural circuit wiring in Drosophila

Abstract

Type IIa receptor-like protein tyrosine phosphatases (RPTPs) are essential for neural development. They have cell adhesion molecule (CAM)-like extracellular domains that interact with cell-surface ligands and coreceptors. We identified the immunoglobulin superfamily CAM Sticks and Stones (Sns) as a new partner for the Drosophila Type IIa RPTP Lar. Lar and Sns bind to each other in embryos and in vitro, and the human Sns ortholog, Nephrin, binds to human Type IIa RPTPs. Genetic analysis shows that Lar and Sns function together to regulate larval neuromuscular junction development, axon guidance in the mushroom body (MB), and innervation of the optic lobe medulla by R7 photoreceptors. In the neuromuscular system, Lar and Sns are both required in motor neurons, and may function as coreceptors. In the MB and OL, however, the relevant Lar-Sns interactions are in trans (between neurons), so Sns functions as a Lar ligand in these systems.

Drosophila noktochor regulates night sleep via a local mushroom body circuit

“… 46 , 47 Also of interest, Lar is expressed in the α/β and γ lobes of the adult MB, with no detectable expression in the α′/β′ lobes. 48 This expression pattern is complementary to the known cellular requirement for NKT in the α′/β′ neurons of the MB and suggests that Lar might serve as a receptor for NKT. Notably, genome-wide association studies and mutant analysis have shown that both Drosophila Lar and its close mammalian ortholog PTPRD are associated with variations in sleep pattern.…”

“…Based on behavioral phenotypes, we suggest that a transmembrane receptor protein tyrosine phosphatase called Lar may mediate NKT action in the MB, although we have not shown direct binding between the two proteins. Lar is expressed in the α/β and γ lobes of the adult MB but not in the α′/β′ lobes, 48 , 53 which require NKT, consistent with a ligand-receptor relationship. Importantly, knockdown or overexpression of Lar in the MB increased or decreased sleep, respectively ( Figures 4 D and 4E), indicating that Lar normally promotes wakefulness.…”

The draft genome of the microscopic Nemertoderma westbladi sheds light on the evolution of Acoelomorpha genomes

“…Regardless of their phylogenetic position, whether as a sister to Ambulacraria or Nephrozoa, the presence of these genes might be explained by their participation in other important functions. A spatial transcriptomics analysis in the acoel Isodiametra pulchra and the nemertodermatid Meara stichopi located the expression of Nephrin in the brain and the nerve cords (Andrikou et al, 2019), which resembles observations in mammals and Drosophila, the latter through the Nephrin homolog Sns (Putaala et al, 2000;Putaala et al, 2001;Bali et al, 2022). In contrast, no homologs to the Osr gene (named Odd in Drosophila) could be annotated in any of the acoelomorph genomes.…”

Synaptic promiscuity in brain development

“…The live observations at the moment of choice indicate that the failure to stabilize is likely due to the primary defect in synapse formation 86 . The intercellular interaction partner of LAR on presynaptic filopodia has not been found, but a candidate interacting cell surface protein has recently been characterized 124 . On the presynaptic side, LAR directly recruits the synaptic seeding factor Liprin-α, as originally characterized in C. elegans 125 .…”