| The genetic role of the zinc finger transcription factor GATA-2 during mouse development is explored. In particular, midbrain formation and megakaryopoiesis are studied in depth. Previously, a requirement for GATA-2 in hematopoietic progenitor development was defined through gene deletion studies in mice. Though GATA-2 is widely expressed, its participation in the development of other tissues remained poorly studied. One aim in this thesis is to study GATA-2's role in brain development. A conditional GATA-2 mouse mutant has been generated for this purpose, using the Cre-loxP system. Specific deletion of GATA-2 in the embryonic midbrain results in abnormal expansion in neonates or young mice, which display runting, seizures, and early death. Analysis of embryonic midbrains indicates defects in proliferation and tectal specification. The second aim in this thesis is to understand developmental consequences of protein-protein interactions in which GATA-2 engages. Mouse knock-in approaches have been used to generate GATA-1 and GATA-2 mutants that specifically cannot bind Friend of GATA-1 (FOG-1). Loss of GATA:FOG interaction results in complete failure of megakaryopoiesis, mirroring the defects seen in FOG-1 knockout mice. This is the first evidence supporting a role for a GATA-2:FOG interaction in development. Taken together, this work illustrates how the mouse genome re-uses transcriptional regulatory proteins in disparate tissue types and regulates their activities by distinct protein-protein combinations. |
