Retinoic acid signaling in perioptic mesenchyme represses Wnt signaling via induction of Pitx2 and Dkk2.
Morphogenesis during eye development requires retinoic acid (RA) receptors plus RA-synthesizing enzymes, and loss of RA signaling leads to ocular disorders associated with loss of Pitx2 expression in perioptic mesenchyme. Several Wnt signaling components are expressed in ocular tissues during eye development including Dkk2, encoding an inhibitor of Wnt/beta-catenin signaling, which was previously shown to be induced by Pitx2 in the perioptic mesenchyme. Here, we investigated potential cross-talk between RA and Wnt signaling during ocular development. Genetic studies using Raldh1/Raldh3 double null mice deficient for ocular RA synthesis demonstrated that Pitx2 and Dkk2 were both down-regulated in perioptic mesenchyme. Chromatin immunoprecipitation and gel mobility shift studies demonstrated the existence of a DR5 RA response element upstream of Pitx2 that binds all three RA receptors in embryonic eye. Axin2, an endogenous readout of Wnt/beta-catenin signaling, was up-regulated in cornea and perioptic mesenchyme of RA deficient embryos. Also, expression of Wnt5a was expanded in perioptic mesenchyme of RA deficient eyes. Our findings demonstrate excessive activation of Wnt signaling in the perioptic mesenchyme of RA deficient mice which may be responsible for abnormal development leading to defective optic cup, cornea, and eyelid morphogenesis.
Kumar
Sandeep
S
Burnham Institute for Medical Research, Development and Aging Program, La Jolla, California 92037, USA.
Duester
Gregg
G
D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D019521:Body Patterning; D004622:Embryo, Mammalian / Q000378:metabolism; D005123:Eye / Q000196:embryology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D050697:Retinal Dehydrogenase; D014157:Transcription Factors; D014212:Tretinoin; D051153:Wnt Proteins; D000097577:Homeobox Protein PITX2; C405060:Dkk2 protein, mouse; C515028:ALDH1A1 protein, mouse; C508905:retinaldehyde dehydrogenase 3, mouse