Drosophila Hematopoeisis

As in mammals, blood cells in Drosophila are derived from a common multipotent hematopoietic precursor population. In the embryo, these precursors are derived from the head mesoderm, whereas larval hematopoietic precursors are found in a specialized organ called the lymph gland. This shift in location of hematopoietic differentiation is reminiscent of similar events that occur during mammalian development. Recent analysis has identified several transcriptional regulators in Drosophila that influence hematopoietic lineage commitment, Interestingly, many of these factos are similar to factors directing mammalian hematopoietic differentiation. Although Drosophila blood cells are much less varied in terms of specific lineages, it would appear that many mechanistic aspects by which hemetopoietic cell fate is determined have been conserved between Drosophila and mammals. In our research, we study Drosophila blood cell types, their physical origin, and the transcriptional regulators that lead to their specification and differentiation.

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The Drosophila compound eye consists of a large number ommatidia (facets) each containing a fixed number of cells: eight photoreceptor cells (R cells), four non-neuronal cone cells, three classes of pigment cells and a bristle complex. The fate of these cells is not derived by clonal mechanisms but through cell-cell communication. The Drosophila eye develops from a sheet of epithelial tissue called the eye imaginal disc. In the third larval instar an indentation called the morphogenetic furrow (MF) initiates at the posterior tip and sweeps anteriorly across the disc. As cells emerge out of the furrow, they attain the competence to respond to signaling pathways and initiate differentiation in a precise order. The photoreceptors are the first cells to differentiate followed by the cone cells and the pigment cells. This led to the hypothesis that unique signals from differentiated cells will sequentially induce the precursors of later developing cell types. The molecular basis for such a combinatorial model is now becoming clear. The biggest surprise is that the signals involved are not very specific and that a small number of common signaling pathways and transcription factors can combine in different ways to generate a tremendous diversity of readouts. The EGFR and Notch signaling pathways are prominently involved in this process. All components of these pathways, except the ligands, are ubiquitously expressed. The spatio-temporal control of the ligand determines the cells in which a mosaic pattern of activated transcription factors is generated. In our research, we study Drosophila eye development in which the Notch and EGFR pathways combine in different ways to generate unique outputs.

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Leukemia is the clonal, malignant proliferation of blood cell progenitors; left untreated, most leukemias are associated with an extremely poor prognosis. Understanding the mechanisms underlying leukemic transformation may ultimately lead to the identification of novel therapeutic targets, as well as insights into the normal processes of hematopoiesis. Like most cancers, leukemia is a multi-step process: a primary genetic lesion results in a proliferative or differentiation defect, followed by secondary genetic events that result in the full-blown malignant condition. By themselves, the primary lesions are not sufficient to cause disease, but instead provide susceptibility to accumulating secondary, disease causing lesions. In most leukemias, the primary lesions are characterized but the genes mutated in secondary stages have yet to be identified.

Hematopoeisis is highly conserved among different vertebrate species. For example zebrafish, a common tropical aquarium fish, have the same types of differentiated blood cells as humans, and many of the same genes are implicated in their formation during human and zebrafish embryogenesis. Zebrafish is an excellent experimental system for genetic and embryological studies. We will exploit the similarities between zebrafish and human hematopoiesis to identify candidates for the genes mutated in the secondary steps of human leukemia. A strain of zebrafish will be engineered for predisposation to acute leukemia due to expression of a human leukemic oncogene in the hematopoietic stem cells. A genetic screen using the leukemia-prone strain will identify mutations in genes that result in full-blown leukemia in combination with the human oncogene. These genes are candidates for genes involved in the secondary stages of human leukemia. These mutations will be mapped, the genes molecularly cloned, and their roles in normal hematopoiesis and leukemia fully characterized. Understanding the function of these leukemia modifier genes and their human counterparts will lead to novel therapies and screening procedures in the clinic.

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