DLX homeobox genes in vertebrate retinal development
David Daniel Eisenstat, M.D., M.A., FRCPC
Department of Ophthalmology, Anatomy and Physiology
University of Manitoba, Winnipeg, Manitoba
After accidents and trauma, the most common causes of blindness in childhood can be attributed to gene mutations and/or disorders of development of the eye. The pathogenesis of blindness due to inherited diseases of the retina is poorly understood. There are few interventions that can maintain or restore an affected child's vision.
The identification of retinal cell-type specific genes that are mutated in inherited diseases has significantly advanced our knowledge of eye development. The Distal-less or D1x homeobox gene family code for transcription factors important for development of the brain and craniofacial structures. The D1x genes are expressed during retinal development and in the adult retina. Loss of both D1x1 and D1x2 gene function in an animal model, the D1x1/D1x2 double knockout mouse, results in abnormal retinal development, especially in the retinal ganglion cells whose axons form the optic nerves that transmit visual inputs to the brain for higher order processing.
This research will determine how D1x genes function in retinal development and maintenance in the adult by ifentifying D1x gene targets specific to the developing retina. We will use a biochemical/molecular technique known as chromatin immunoprecipitation (ChIP) that we have previously optimized to characterize D1x gene targets in the developing forebrain. As well, since retinal development proceeds beyond the day of birth in the mouse (when the D1x1/D1x2 double knockout mouse dies), we will develop a conditional knockout of both D1x1 and D1x2 function only in the developing retina using well-established gene technology, the Cre-lox system. This "designer" knockout mouse will survive into adulthood and is expected to have abnormal retinal development and function. This retinal tissue-specific D1x1/D1x2 null mouse may serve as an animal model of human congenital retinal disease. Moreover, identifying D1x gene targets specific to the retina may lead to novel therapies of retinal diseases due to birth defects in humans.