Signaling And Transcription Regulation In Nervous System

Neurological Disorders And Stroke

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Abstract

Using genetic, biochemical and cell biological methods, we are addressing two fundamental questions in developmental biology: what are the mechanisms that govern the generation of individual cell lineages, and how do cell lineages come together to form a functioning organ? We focus our studies on two organ systems, the eye and the neural crest, and concentrate on key transcriptional regulators that link extracellular cues to the program of gene expression. In the developing eye, we are studying a set of transcription factors that regulate the separation of the initially homogeneous and pluripotent optic neuroepithelium into the distinct domains that go on to form the multilayered retina, the retinal pigment layer, the iris, and the optic nerve. In particular, we are analyzing how factors such as Mitf, Chx10 and Vax1/2 gain, and then maintain, characteristic complementary expression patterns and effect the distal/proximal and dorsal/ventral polarities of the developing optic cup. A particular effort goes into the analysis of Mitf which plays essential roles in pigment cell development and whose mutations lead to eye abnormalities and deafness since pigment cells are critical in eye and inner ear development and function. Mitf is encoded by a gene with multiple promoters and a variety of splicing patterns that give rise to many distinct isoforms. Our studies have identified pantropic as well as eye domain-specific isoforms whose roles and regulations we are currently dissecting in mice with targeted mutations in distinct promoters and specific exons. Besides its regulation at the transcriptional level, Mitf is also regulated by post-translational modifications including sumoylations and phosphorylations that may modify its interactions with transcriptional co-regulators. In particular, signaling-dependent phosphorylation at two serines has been implicated in regulating MITF activity and stability. We found that mutations in a phosphorylation site affect pigment cell proliferation and differentiation in vitro, but, based on a line of mice with a corresponding targeted mutation, apparently only in the neural crest- and not the optic neuroepithelium. These and additional mutational and biochemical studies highlight the importance of distinct transcription factor isoforms and suggest that they fulfill discrete tasks in sensory organ development and function.