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Contribution of retinoic acid receptor gamma to retinoid‐induced craniofacial and axial defects
Author(s) -
Iulianella Angelo,
Lohnes David
Publication year - 1997
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/(sici)1097-0177(199705)209:1<92::aid-aja9>3.0.co;2-s
Subject(s) - biology , retinoic acid , retinoid , hox gene , craniofacial , endocrinology , medicine , retinoic acid receptor , morphogenesis , homeotic gene , axial skeleton , receptor , mutant , microbiology and biotechnology , anatomy , genetics , gene expression , gene
Exogenous retinoic acid (RA) administered during mouse embryogenesis can alter the pattern of the axial skeleton during two developmental periods: an early window (7 to 8.5 days post‐coitum; dpc) and a late window (9.5 to 11.5 dpc). Treatment during the early window results in vertebral homeotic transformations (predominantly posteriorizations) concomitant with rostral shifts in Hox gene expression, while treatment at the later window results in similar transformations without detectable alterations in Hox gene expression patterns. Mice null for retinoic acid receptor gamma (RARγ) exhibit axial defects, including homeosis of several vertebrae, therefore establishing a role for this receptor in normal axial specification. RARγ null mutants are also completely resistant to RA‐induced spina bifida, which occurs in wildtype embryos treated at 8.5–9.0 dpc, suggesting that this receptor specifically transduces at least a subset of the teratogenic effects of retinoids. To further investigate the role of RARγ in RA‐induced defects during the early and late windows of retinoid‐sensitive vertebral patterning, RARγ heterozygotes were intercrossed, pregnant females treated with vehicle or RA at 7.3, 10.5 or 11.5 dpc and full‐term fetuses assessed for skeletal defects. Relative to wildtype littermates, RARγ null mutants treated at 7.3 dpc were markedly resistant to RA‐induced embryolethality, craniofacial malformations, and neural tube defects. Furthermore, while RARγ null mutants were modestly resistant to certain vertebral malformations elicited by RA treatment at 7.3, they exhibited more pronounced resistance following treatment at 10.5 and 11.5 dpc. Moreover, several of the vertebral defects inherent to the RARγ null phenotype were abolished by RA treatment specifically at 10.5 dpc, suggesting that RARα and/or RARβ isoforms may substitute for certain RARγ functions, and that RARγ may elicit its normal effects on vertebral morphogenesis at this developmental stage. Dev. Dyn. 209:92–104, 1997. © 1997 Wiley‐Liss, Inc.