The zebrafish retinol dehydrogenase, rdh1l, is essential for intestinal development and is regulated by the tumor suppressor adenomatous polyposis coli.
Retinoic acid (RA) is a potent signaling molecule that plays important roles in multiple and diverse developmental processes. The contribution of retinoic acid to promoting the development and differentiation of the vertebrate intestine and the factors that regulate RA production in the gut remain poorly defined. Herein, we report that the novel retinol dehydrogenase, rdh1l, is required for proper gut development and differentiation. rdh1l is expressed ubiquitously during early development but becomes restricted to the gut by 3 days postfertilization. Knockdown of rdh1l results in a robust RA-deficient phenotype including lack of intestinal differentiation, which can be rescued by the addition of exogenous retinoic acid. We report that adenomatous polyposis coli (APC) mutant zebrafish harbor an RA-deficient phenotype including aberrant intestinal differentiation and that these mutants can be rescued by treatment with retinoic acid or injection of rdh1l mRNA. Further, we have found that although APC mutants are deficient in rdh1l expression, they harbor increased expression of raldh2 suggesting the control of RA production by APC is via retinol dehydrogenase activity. These results provide genetic evidence that retinoic acid is required for vertebrate gut development and that the tumor suppressor APC controls the production of RA in the gut by regulating the expression of the retinol dehydrogenase, rdh1l.
Nadauld
Lincoln D
LD
Department of Oncological Sciences, University of Utah, Salt Lake City 84112, USA.
Shelton
Dawne N
DN
Chidester
Stephanie
S
Yost
H Joseph
HJ
Jones
David A
DA
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000429:Alcohol Oxidoreductases / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000196:embryology / Q000201:enzymology*; D009154:Mutation; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000502:physiology*
D025601:Adenomatous Polyposis Coli Protein; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D014212:Tretinoin; D012313:RNA; D000429:Alcohol Oxidoreductases; C504258:rdh12 protein, zebrafish; C022520:retinol dehydrogenase