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Functional Conservation of the Glide/Gcm Regulatory Network Controlling Glia, Hemocyte, and Tendon Cell Differentiation in Drosophila.



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Cattenoz, Pierre B 
Popkova, Anna 
Southall, Tony D 
Aiello, Giuseppe 
Brand, Andrea H 


High-throughput screens allow us to understand how transcription factors trigger developmental processes, including cell specification. A major challenge is identification of their binding sites because feedback loops and homeostatic interactions may mask the direct impact of those factors in transcriptome analyses. Moreover, this approach dissects the downstream signaling cascades and facilitates identification of conserved transcriptional programs. Here we show the results and the validation of a DNA adenine methyltransferase identification (DamID) genome-wide screen that identifies the direct targets of Glide/Gcm, a potent transcription factor that controls glia, hemocyte, and tendon cell differentiation in Drosophila. The screen identifies many genes that had not been previously associated with Glide/Gcm and highlights three major signaling pathways interacting with Glide/Gcm: Notch, Hedgehog, and JAK/STAT, which all involve feedback loops. Furthermore, the screen identifies effector molecules that are necessary for cell-cell interactions during late developmental processes and/or in ontogeny. Typically, immunoglobulin (Ig) domain-containing proteins control cell adhesion and axonal navigation. This shows that early and transiently expressed fate determinants not only control other transcription factors that, in turn, implement a specific developmental program but also directly affect late developmental events and cell function. Finally, while the mammalian genome contains two orthologous Gcm genes, their function has been demonstrated in vertebrate-specific tissues, placenta, and parathyroid glands, begging questions on the evolutionary conservation of the Gcm cascade in higher organisms. Here we provide the first evidence for the conservation of Gcm direct targets in humans. In sum, this work uncovers novel aspects of cell specification and sets the basis for further understanding of the role of conserved Gcm gene regulatory cascades.



DamID, Drosophila, glide/gcm, mGcm, screen, Animals, Binding Sites, Cell Differentiation, Cell Line, Conserved Sequence, DNA, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Feedback, Physiological, Genetic Techniques, HeLa Cells, Hemocytes, Humans, Neuroglia, Signal Transduction, Site-Specific DNA-Methyltransferase (Adenine-Specific), Transcription Factors

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Oxford University Press (OUP)
Wellcome Trust (092545/Z/10/Z)
Wellcome Trust (092096/Z/10/Z)
Wellcome Trust (068055/Z/02/Z)
Cancer Research Uk (None)
Wellcome Trust (103792/Z/14/Z)
We thank the DHSB and the Bloomington Stock Center for reagents and flies as well as J. Veenstra (INCIA UMR 5287 CNRS, France) for the gift of the Anti-DH31 antibody and B. Altenhein (U Mainz, Germany) for fly strains. We thank K. Jamet for initial bioinformatics analyses. We thank C. Diebold, C. Delaporte, and IGBMC facilities for technical assistance. We thank the members of the lab for valuable input and comments on the manuscript. This work was supported by INSERM, CNRS, UDS, Hôpital de Strasbourg, ARC, INCA and ANR grants. A. Popkova and P. Cattenoz were funded by the FRM and by the ANR, respectively. A. Popkova also benefitted from a short Development traveling fellowship to visit the laboratory of A. Brand in Cambridge (UK). The IGBMC was also supported by a French state fund through the ANR labex. T.D.S and A.H.B were funded by Wellcome Trust Programme Grants 068055 and 092545 to A.H.B. A.H.B acknowledges core funding to the Gurdon Institute from the Wellcome Trust (092096) and CRUK (C6946/A14492).