Retinoic Acid Antagonism of Fgf8 during Forelimb Development

Abstract

Retinoic acid (RA) in the proximal limb is purported to act as a proximal signal during proximodistal patterning of chick limbs, however this remains controversial as it is not supported by genetic findings in mouse. Using a RARE‐lacZ RA‐reporter transgene (which we show to be sensitive to 2.5 nM RA) we found that mouse embryos lacking retinol dehydrogenase‐10 (Rdh10) lost all RA activity in fore‐ and hindlimb fields although they retain RA activity in posterior neuroectoderm. Although forelimbs were stunted, Rdh10 mutant hindlimbs were normal, and both expressed key patterning genes in the correct spatiotemporal pattern. Previous studies on Raldh2 mutants have shown that RA antagonizes Fgf8 and that excessive FGF signaling in both primitive streak and cardiac domains blocks forelimb initiation. Here, we show that Rdh10 mutants exhibit ectopic Fgf8 expression only posterior to the heart where the forelimb field arises, suggesting a mechanism for how stunted forelimbs arise. We propose that while RA does not pattern the forelimb itself, axial heart RA‐Fgf8 antagonism is required prior to forelimb field formation to provide an environment permissive for normal budding and patterning of the forelimb.