Neurotrophic activities of trk receptors conserved over 600 million years of evolution

Abstract

The trk family of receptor tyrosine kinases is crucial for neuronal survival in the vertebrate nervous system, however both C. elegans and Drosophila lack genes encoding trks or their ligands. The only invertebrate representative of this gene family identified to date is Ltrk from the mollusk Lymnaea. Did trophic functions of trk receptors originate early in evolution, or were they an innovation of the vertebrates? Here we show that the Ltrk gene conserves a similar exon/intron order as mammalian trk genes in the region encoding defined extracellular motifs, including one exon encoding a putative variant immunoglobulin-like domain. Chimeric receptors containing the intracellular and transmembrane domains of Ltrk undergo ligand-induced autophosphorylation followed by MAP kinase activation in transfected cells. The chimeras are internalized similarly to TrkA in PC12 cells, and their stimulation leads to differentiation and neurite extension. Knock-down of endogenous Ltrk expression compromises outgrowth and survival of Lymnaea neurons cultured in CNS-conditioned medium. Thus, Ltrk is required for neuronal survival, suggesting that trophic activities of the trk receptor family originated before the divergence of molluscan and vertebrate lineages approximately 600 million years ago.

Drosophila neurotrophins reveal a common mechanism for nervous system formation

“…Our findings and those of others [33][34][35][36]38,41,45] suggest that the evolution of neurotrophin signalling may have resulted in diversification of receptors and/or downstream signalling pathways.…”

“…NT ligands and receptors have been identified throughout the invertebrate deuterostomes ( Figure S1). There are functional Trk receptors in the lancelet Amphioxus [33], and p75 and Trk orthologs have been identified in sea urchin and acorn worm [34][35][36]. Searches of sequenced genomes have revealed NTs in all deuterostome groups, represented by Amphioxus NT (Bf-NT), acorn worm NT (Sk-NT), and sea urchin NT (Sp-NT) [34,37,38] ( Figure S1 and Table S1).…”

A novel cysteine-rich neurotrophic factor in Aplysia facilitates growth, MAPK activation, and long-term synaptic facilitation

“…Although to date no Trk receptors have been reported in Drosophila or C. elegans, several Trk or Trk-like receptors have been identified in mollusks (Beck et al 2004;Ormond et al 2004;Kassabov et al 2013). LTrk, a prototypical Trk receptor in Lymnaea, is required in neuronal survival and outgrowth (Beck et al 2004).…”

“…LTrk, a prototypical Trk receptor in Lymnaea, is required in neuronal survival and outgrowth (Beck et al 2004). In Aplysia, in addition to the two aforementioned neurotrophins, ApNT (Kassabov et al 2013) and apCRNF (described here), two Trk receptors, ApTrkl and ApTrk, have been identified (Ormond et al 2004;Kassabov et al 2013).…”

Differential Proteomics Reveals Multiple Components in Retrogradely Transported Axoplasm After Nerve Injury

“…The PCR product was then used as a template for transcription of double-stranded RNA (dsRNA) using T7 RNA Polymerase (Roche Molecular Biochemicals). The dsRNA was applied to a final concentration of 10 pM in cultures of L. stagnalis PedalA neurons as previously described (20). Cultured neurons were incubated in a dark humidified chamber for up to 72 h and scored for neurite sprouting under an inverted microscope (Axiovert 135; Zeiss, Thornwood, NY).…”