| Runx proteins are important regulators of many key developmental processes in invertebrates and vertebrates. Loss of proper Runx protein function has been implicated in leukemia, cleidocranial dysplasia, and stomach cancer. Runx proteins are widely expressed and control the expression of cell-specific transcription factors through both positive and negative transcriptional regulation. Here, studies on the Drosophila Runx proteins, Runt and Lozenge (Lz), were conducted to better understand their roles in development and cell-fate determination.; Photoreceptors in the Drosophila eye project their axons to one of two layers in the optic lobe. The axons of the R1-R6 photoreceptors terminate in the lamina, while the R7/R8 axons terminate in the medulla. We investigated the relationship between Runt, which is expressed in R7/R8 cells, and Brakeless (Bks), which is required for R1-R6 axon termination in the lamina. In bks mutants, R1-R6 axons mistarget to the medulla. We show that the function of Bks is to repress Runt in two R cells, and that loss of Runt repression in those two cells causes severe axonal mistargeting of all axons of R1-R6 neurons. This study has implications for the pioneering role of certain R cell axons, and highlights the control of axonal targeting decisions through repression, transcriptional events that are separable to those that control cell fate decisions.; Lz is expressed in a pool of undifferentiated precursors in the developing eye, and by controlling the expression of several other cell-specific transcription factors, controls the patterning of cells into a multitude of distinct cell types. Previously, it was shown that Lz acts as a direct transcriptional activator and works in combination with effectors of general signaling pathways. Here, the mechanism of negative regulation by Lz is investigated. Through genetic and biochemical analyses, we describe a developmental circuit whereby Lz causes activation of the homeodomain protein Cut, which can then stabilize a Lz repressor complex in the same cell. Whether a gene is activated or repressed is determined by whether the Lz activator or the repressor complex binds to its upstream sequence. This study provides a mechanistic basis for the dual function of Runx proteins that is likely to be conserved in mammalian systems. |
