Increased avidity for Dpp/BMP2 maintains the proliferation of eye progenitors in Drosophila

During normal organ development, the progenitor cell state is transient: it depends on specific combinations of transcription factors and extracellular signals, that cooperate to sustain the proliferative potential and undifferentiated status of organ progenitor cells. Not surprisingly, abnormal maintenance of progenitor transcription factors may lead to tissue overgrowth, and the concurrence of specific signals from the local environment is often critical to trigger this overgrowth. Therefore, the identification of the specific combinations of transcription factors and signals that promote or oppose proliferation in progenitor cells is essential to understand normal development and disease. We have investigated this issue by asking what signals may promote the proliferation of eye progenitors in Drosophila. Two transcription factors, the MEIS1 homologue homothorax (hth) and the Zn-finger teashirt (tsh) are transiently expressed in eye progenitors causing the expansion of the progenitor pool. However, if their co-expression is maintained experimentally, cell proliferation continues and differentiation is halted. Here we show that Hth+Tsh-induced tissue overgrowth requires the BMP2 ligand Dpp and the activation of its pathway. In Hth+Tsh cells, the Dpp pathway is abnormally hyperactivated. Rather than using autocrine Dpp expression, Hth+Tsh cells increase their avidity for Dpp, produced locally, by upregulating extracellular matrix components. During normal development, Dpp represses hth and tsh ensuring that the progenitor state is transient. However, cells in which Hth+Tsh expression is maintained use Dpp to enhance their proliferation.\n\nSummary StatementIn Drosophila, homothorax, the Meis1 homologue, and teashirt jointly sustain the proliferation of eye progenitor cells by increasing their avidity for BMP produced by the local microenvironment.