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J. Matter, J. Hernandez, L. Matter-Sadzinski, F.N. Riva, M. Ballivet; bHLH Factors Regulate ATH5 Expression in the Developing Retina . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1600.
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Purpose: We are interested in the developmental mechanisms whereby retina progenitor cells acquire the ganglion cell (RGC) fate. In several vertebrate species, ATH5 is transiently expressed in a defined region during retinal development and its function is essential for the genesis of RGCs. In mice and zebrafish, loss of ATH5 gene function results in the absence of both the RGC population and the optic nerve. In the chick embryo, gain of function studies have shown that ATH5 is able to induce the expression of RGC-specific genes (e.g., ß3nAChR, Brn3c). We cloned the chick ATH5 ortholog and found its expression to be transient early in development and restricted to proliferating cells of the neuroepithelium and to newborn RGCs (Matter-Sadzinski et al. 2001; Development, 128:217-231). Here, we focus on the identification of ATH5 cis-regulatory sequences and their contribution to the ATH5 gene-expression pattern during retina development. Methods: ATH5 promoter properties were analyzed, in vivo, by electroporation of the chick retina and, in vitro, by lipofection of dissociated retinal cells. Results: In the upstream region of the ATH5 gene we found seven E-boxes, among other regulatory sequences. Since E-boxes are the consensus binding sequences for basic helix-loop-helix (bHLH) transcription factors, we tested the ability of a number of bHLH factors cloned from the early retina to transactivate the ATH5 promoter. We found that ngn2, NeuroM and ATH5 itself strongly enhance ATH5 expression in the early retina but fail to do so later on in development. Two other bHLH proteins, ASH1 and HES1, whose retinal expression domains complement that of ATH5, exert a very strong dominant-negative control over the ATH5 promoter. A detailed mutational analysis of the E-boxes shows that ATH5 is differentially regulated during development through specific interactions of these bHLH proteins with the different E-boxes. Conclusion: A cascade of interacting bHLH factors regulates ATH5 transcription.
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