Highly conserved sequences mediate the dynamic interplay of basic helix-loop-helix proteins regulating retinogenesis.
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.
Hernandez
Julio
J
Department of Biochemistry, Sciences II and Department of Ophthalmology, School of Medicine, University of Geneva, 1211, Genève 4, Switzerland.
Matter-Sadzinski
Lidia
L
Skowronska-Krawczyk
Dorota
D
Chiodini
Florence
F
Alliod
Christine
C
Ballivet
Marc
M
Matter
Jean-Marc
JM
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
D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA