title: Highly conserved sequences mediate the dynamic interplay of basic helix-loop-helix proteins regulating retinogenesis.
abstract: The atonal homolog 5 (ATH5) protein is central to the transcriptional network regulating the specification of retinal ganglion cells, and its expression comes under the spatiotemporal control of several basic helix-loop-helix (bHLH) proteins in the course of retina development. Monitoring the in vivo occupancy of the ATH5 promoter by the ATH5, Ngn2, and NeuroM proteins and analyzing the DNA motifs they bind, we show that three evolutionarily conserved E-boxes are required for the bHLH proteins to control the different phases of ATH5 expression. E-box 4 mediates the activity of Ngn2, ATH5, and NeuroM along the pathway leading to the conversion of progenitors into newborn neurons. E-box 1, by mediating the antagonistic effects of Ngn2 and HES1 in proliferating progenitors, controls the expansion of the ATH5 expression domain in early retina. E-box 2 is required for the positive feedback by ATH5 that underlies the up-regulation of ATH5 expression when progenitors are going through their last cell cycle. The combinatorial nature of the regulation of the ATH5 promoter suggests that the bHLH proteins involved have no assigned E-boxes but use a common set at which they either cooperate or compete to finely tune ATH5 expression as development proceeds.
authors.affiliation: Department of Biochemistry, Sciences II and Department of Ophthalmology, School of Medicine, University of Geneva, 1211, Genève 4, Switzerland.
authors.forename: Julio
authors.initials: J
authors.lastname: Hernandez
authors.forename: Lidia
authors.initials: L
authors.lastname: Matter-Sadzinski
authors.forename: Dorota
authors.initials: D
authors.lastname: Skowronska-Krawczyk
authors.forename: Florence
authors.initials: F
authors.lastname: Chiodini
authors.forename: Christine
authors.initials: C
authors.lastname: Alliod
authors.forename: Marc
authors.initials: M
authors.lastname: Ballivet
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Matter
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry*; D002453:Cell Cycle; D049109:Cell Proliferation; D002642:Chick Embryo; D017124:Conserved Sequence; D004247:DNA / Q000737:chemistry; D005724:Ganglia / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012160:Retina / Q000196:embryology* / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA