The last decade has been marked by the deciphering of whole genome sequence in numerous species. Recent advances in transcriptomics further reveal that an unexpectedly large proportion of our genome produces atypical RNAs that, unlike mRNAs, do not encode proteins. From seminal works in nematodes, it is well now established that short non-coding RNAs (ncRNA), including microRNAs, play key roles in the control of development and differentiation. In addition, experimental cases show that large (>1kb) non-coding RNAs can contribute as well to various regulatory functions in the control of gene expression. The role and mode of action of large RNAs that do not encode proteins remains however poorly understood. Therefore, a major challenge resides in understanding the molecular and developmental functions of this novel class of RNAs. Most large RNAs nevertheless comprise small Open-Reading-Frames (smORF) that, precisely because of their small size, are generally considered as being non-functional and filtered off from annotations. However, at least some of these smORF may encode peptides, the abundance of which is probably underestimated. We have recently discovered that the Polished-rice (Pri) small peptides (11-32aa) encoded by an alleged “ncRNA” play a critical role in the control of transcriptional programs during the Drosophila development. These atypical small peptides therefore represent the first case of a novel regulatory mechanism. Several evidence support that small peptides encoded by apparently ncRNA fulfill additional roles in regulating development and differentiation, but their abundance, functional repertoire and mode of action remains entirely to be elucidated. We aim to address these questions by a combination of large scale functional and bio-informatics approaches in Drosophila. Our team is a recognized leader in the study of epidermal differentiation during Drosophila embryogenesis, as a paradigm of cell morphogenesis. Previous works have established the importance of the Shavenbaby Transcription Factor that determines, in a robust manner, the precise subset of epidermal cells forming apical extensions, referred to as trichomes. Consistently, independent modifications of Svb expression have caused diversification of trichome patterns throughout the evolution of insects. Shavenbaby directly activates the transcription of various cell effectors, collectively responsible for trichome cell morphogenesis. We have recently found that the transcriptional activity of the Svb protein is controlled by Polished-rice small peptides. During embryogenesis, Pri trigger the N-terminal truncation of the Svb protein, switching its activity from a (full length) Repressor an (truncated) Activator. Importantly, we obtained suitable conditions to transfer this functional interaction between Pri peptides and the Svb Transcription Factor in stable cell lines, providing a unique opportunity to explore the molecular mechanisms underlying this novel aspect of the control of genome expression. Based on accumulated biological tools and a collaborative network with international specialists, this research program aims at unraveling how small peptides control multiple steps of the Drosophila development. Our specific goals are to: 1) provide compelling insights into the molecular determinants and cellular factors mediating Pri peptides activity on the truncation of the Svb transcription factor, 2) identify additional cellular functions and the corresponding regulators that are targeted by Pri peptides during Drosophila development, 3) use Pri as a paradigm to explore the repertoire of small peptides putatively encoded by similar apparently non-coding RNAs.