The pleiotropic functions of Pri smORF peptides synchronise leg development regulators

Abstract

The last decade witnesses the emergence of the abundant family of smORF peptides, encoded by small ORF (<100 codons), whose biological functions remain largely unexplored. Bioinformatic analyses here identify hundreds of putative smORF peptides expressed in Drosophila imaginal leg discs. Thanks to a functional screen in legs, we found smORF peptides involved in morphogenesis, including the pioneer smORF peptides Pri. Since we identified its target Ubr3 in the epidermis and pri was known to control leg development through misunderstood mechanisms, we investigated the role of Ubr3 in mediating pri function in legs. We found that pri play several roles during leg development both in patterning and in cell survival. At larval pupal transition, Pri peptides cooperate with Ubr3 to insure cell survival and leg morphogenesis. Earlier, during larval stage, pri activates independently of Ubr3 tarsal transcriptional programs and Notch and EGFR signalling pathways. Our results highlight Ubr3 dependent and independent functions of Pri peptides and their pleiotropy. Moreover, we reveal that the smORF peptide family is a reservoir of overlooked developmental regulators, displaying distinct molecular functions and orchestrating leg development.

Pri peptides temporally coordinate transcriptional programs during epidermal differentiation

“…Pri peptides are encoded by a gene that is a direct target of the ecdysone receptor (16,41), and they have recently been found to mediate ecdysone action in a growing number of developmental and physiological contexts (24,25,(41)(42)(43). In most cases, Pri peptides play a key role in cell and tissue morphogenesis that involves actin cytoskeleton remodeling (17,18,(22)(23)(24)(25)44).…”

“…Pri peptides are encoded by a gene that is a direct target of the ecdysone receptor (16,41), and they have recently been found to mediate ecdysone action in a growing number of developmental and physiological contexts (24,25,(41)(42)(43). In most cases, Pri peptides play a key role in cell and tissue morphogenesis that involves actin cytoskeleton remodeling (17,18,(22)(23)(24)(25)44). Our findings show that, in the same epidermal cells, Pri temporally controls two independent transcriptional programs, via Svb for actin-based trichomes and via Ken for cuticle properties.…”

“…Besides trichomes (17,18), Pri peptides are known to control the formation of supracellular actin structures called taenidia (18,23), which shape the respiratory system in flies (24). pri is also required for adult leg development, in particular the formation of tarsal joints (17,(25)(26)(27), which involves a marked reorganization of cell shape and of the actin cytoskeleton. A survey of the putative function of genes repressed by pri, using Gene Ontology (GO) classification and Gorilla software, did not show enrichment in actin-related genes (fig.…”

Beyond the Genome: Microproteins Unveiling New Dimensions in Cancer

“…The idea for searching functional microproteins in humans kick started from the insect developmental biology world [12]. While investigating the mRNAs involved in normal development, researchers had uncovered a gene regulating called polished-rice or Tarsal-less (pri/tal), encoding four smORFs that had translated one 32-amino acid and three 11 amino acid microproteins that regulates fly development [37]. This had laid foundation for the hypothesis that genomes harbor important smORFs and that these smORFs produce functional microproteins.…”