The work proposed here is intended to elucidate the mechanism by which the zebrafish Imo4 genes regulate the determination of cells and the organization of the eye, and the development of normal pigmentation. The fish Imo4 are highly related to their mammalian orthologs, and are expressed in similar domains, suggesting that the findings here will be applicable to human development. Reduction of Imo4 activity leads to eye defects that are similar to human coloboma of the optic fissure, a leading cause of human blindness. Therefore understanding how Imo4 functions will advance an understanding of the etiology of coloboma and may have implications for detection and prevention as well. ? ? LMO proteins serve as molecular adaptors for transcription factor complexes, mediating specific protein-protein interactions. The proposed work will investigate the mechanism and significance of those interactions for eye development, using zebrafish genetics, embryo manipulation and molecular biology.
The first aim i s to uncover the precise role of Imo4 activity in eye and pigment development, with emphasis on determining how these two processes are connected at the molecular level. This is significant, as visual impairment and pigmentation abnormalities often co-present in human syndromes, and this work will elucidate mechanisms underlying that linkage. The second, third and fourth aims are to determine how expression and activity of zebrafish LMO4 proteins are regulated at the level of transcription and protein-protein interactions. These experiments will connect Imo4 activity to Fibroblast Growth Factor signaling. ? ? This work will directly impact studies of developmental abnormalities affecting the visual system and pigmentation. In addition, the elucidation of the mechanism of LMO4 function and regulation will be applicable to understanding several forms of cancer, as LMO proteins, including LMO4, are found to be overexpressed by chromosomal translocations associated with acute lymphoblastic leukemia and breast cancer. ? ?
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