The Basic Domain of ATH5 Mediates Neuron-Specific Promoter Activity during Retina Development

Abstract

In the developing retina, the gene encoding the β3 subunit of the neuronal nicotinic receptor, a specific marker of retinal ganglion cells, is under the direct control of the atonal homolog 5 (ATH5) basic helix-loop-helix (bHLH) transcription factor. Although quite short (143 bp in length), the β3 promoter has the remarkable capacity to discriminate between ATH5 and the other neuronal bHLH proteins expressed in the developing nervous system. We have identified three amino acids within the basic domain that confer specificity to the ATH5 protein. These residues do not mediate direct DNA binding but are required for interaction between ATH5 and chromatin-associated proteins during retina development. When misexpressed in neurons, the myogenic bHLH factor MyoD is also able to activate the β3 gene. This, however, is achieved not by binding of the protein to the promoter but by dimerization of MyoD with a partner, a process that depends not on the basic domain but on the HLH domain. By sequestering an E-box-binding protein, MyoD relieves the active repression that blocks the β3 promoter in most neurons. The mechanisms used by bHLH proteins to activate β3 thus highlight how ATH5 is selected by the β3 promoter and coordinates the derepression and transcriptional activation of the β3 gene during the specification of retinal ganglion cells.

ACKNOWLEDGMENTS

We thank Michèle Geindre and Christine Alliod for technical assistance. We are indebted to Làszlò Tora for a generous gift of anti-TBP antibody.

The Swiss National Science Foundation, the Eye Hospital Jules Gonin, the Marguerite Vuilleumier Foundation, the Pro Visu Foundation and the State of Geneva support our laboratories.