During development, stem cells (SCs) proliferate and acquire a cellular identity that guarantees their function. This process is the result of a stereotyped temporal regulation of gene expression (genetic programmes) by temporal mechanisms grouped under the term: temporal patterning. During the embryonic and fetal stages, the proliferation/differentiation balance of SCs must be precisely regulated in time in order to prevent, for example, the formation of abnormally small organs or the development of cancers. However, although actively studied, the mechanisms that determine when a SC must stop proliferating to differentiate are still poorly understood
Using the Drosophila model, our laboratory has identified in recent years various temporal genetic programmes that control the proliferation of SCs and then promote their differentiation in different tissues. Despite their differences, these programs share at their core two antagonistic transcription factors: Chinmo and Broad. Chinmo is expressed during the early stages of development and promotes cell growth and proliferation while repressing differentiation. In contrast, Broad is expressed during late stages and is required to initiate differentiation programs. The Chinmo>Broad transition is induced in various epithelial tissues by a steroid hormone called ecdysone, whose pulses regulate the developmental progression. In the central nervous system (CNS), however, it is the progressive induction of an RNA binding protein, Syp, that induces this transition. Importantly, we and other teams have also shown that chinmo promotes regeneration and is overexpressed in a wide range of Drosophila developmental cancer models. However, its molecular role remains unclear. The aim of my thesis project was to refine our knowledge of the nature and mode of action of the mechanisms involved in temporal patterning during the early stages of development.
My work, using the wing imaginal disc epithelium as a model, has shown that Syp, unlike its role in the CNS, does not induce the Chinmo>Broad transition and is not required for the unfolding of genetic differentiation programs. Instead, Syp is induced by this same transition and is necessary for the establishment of cell physiology and tissue morphology. In particular, in response to Syp inactivation, injured and surrounding cells activate the JAK/STAT pathway which in turn maintains chinmo expression, temporarily blocking the transition and thus maintaining the proliferative capacities of epithelial progenitors. Thus, this work highlights the existence of feedback loops between temporal patterning, physiology and/or morphogenetic processes operating in developing tissues. This mechanism could allow the integrity of tissues under construction to be checked, and errors to be corrected by temporarily maintaining the undifferentiated and proliferative state conferred by Chinmo in order to induce regeneration of the injured tissue.
My results have also advanced our understanding of the mode of action of Chinmo and Broad, suggesting that these major developmental transcription factors constrain the unfolding of genetic differentiation programs through a progressive remodeling of the chromatin landscapes guiding the transcriptional regulatory activity of the ecdysone receptor. This suggests a major role for chromatin remodeling in coordinating growth and tissue specification with developmental progression induced by the ecdysone signaling pathway.