Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development.
Congenital hypertrophy/hyperplasia of the retinal pigmented epithelium is an ocular lesion found in patients harboring mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. We report that Apc-deficient zebrafish display developmental abnormalities of both the lens and retina. Injection of dominant-negative Lef reduced Wnt signaling in the lens but did not rescue retinal differentiation defects. In contrast, treatment of apc mutants with all-trans retinoic acid rescued retinal differentiation defects but had no apparent effect on the lens. We identified Rdh5 as a retina-specific retinol dehydrogenase controlled by APC. Morpholino knockdown of Rdh5 phenocopied the apc mutant retinal differentiation defects and was rescued by treatment with exogenous all-trans retinoic acid. Microarray analyses of apc mutants and Rdh5 morphants revealed a profound overlap in the transcriptional profile of these embryos. These findings support a model wherein Apc serves a dual role in regulating Wnt and retinoic acid signaling within the eye and suggest retinoic acid deficiency as an explanation for APC mutation-associated retinal defects such as congenital hypertrophy/hyperplasia of the retinal pigmented epithelium.
Nadauld
Lincoln D
LD
Department of Oncological Sciences and Medicinal Chemistry and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Chidester
Stephanie
S
Shelton
Dawne N
DN
Rai
Kunal
K
Broadbent
Talmage
T
Sandoval
Imelda T
IT
Peterson
Peter W
PW
Manos
Elizabeth J
EJ
Ireland
Chris M
CM
Yost
H Joseph
HJ
Jones
David A
DA
D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005123:Eye / Q000187:drug effects / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D006720:Homozygote; D008845:Microinjections; D008969:Molecular Sequence Data; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D016376:Oligonucleotides, Antisense; D051153:Wnt Proteins; D014212:Tretinoin