Small ORFs, Big Insights: Drosophila as a Model to Unraveling Microprotein Functions

Recently developed experimental and computational approaches to identify putative coding small ORFs (smORFs) in genomes have revealed thousands of smORFs localized within coding and non-coding RNAs. They can be translated into smORF peptides or microproteins, which are defined as less than 100 amino acids in length. The identification of such a large number of potential biological regulators represents a major challenge, notably for elucidating the in vivo functions of these microproteins. Since the emergence of this field, Drosophila has proved to be a valuable model for studying the biological functions of microproteins in vivo. In this review, we outline how the smORF field emerged and the nomenclature used in this domain. We summarize the technical challenges associated with identifying putative coding smORFs in the genome and the relevant translated microproteins. Finally, recent findings on one of the best studied smORF peptides, Pri, and other microproteins studied so far in Drosophila are described. These studies highlight the diverse roles that microproteins can fulfil in the regulation of various molecular targets involved in distinct cellular processes during animal development and physiology. Given the recent emergence of the microprotein field and the associated discoveries, the microproteome represents an exquisite source of potentially bioactive molecules, whose in vivo biological functions can be explored in the Drosophila model.