Development of Limbs, Respiratory System and Other Systems.
Retinoids have long been linked to vertebrate limb morphogenesis, mainly as the result of studies involving induction of genes and morphologic anomalies with exogenous retinoids. Results from these numerous studies have been summarized in several recent publications which detail the morphology and the genetic pathways and propose mechanisms for retinoid involvement (4 ,5 ,8 ,40) . Recent examination of limb patterning in a physiologically relevant model suggests that studies with ectopic retinoids may not accurately reflect the function of vitamin A in normal limb development (40 ,41) . The completely VAD quail embryo does not live long enough to develop limbs, but in contrast to earlier notions, the initiation of limb bud development occurs in the absence of vitamin A. Analysis of the expression of developmental genes in these limb buds has revealed an important role for vitamin A in patterning the dorsoventral axis (40) . It is not clear how the abnormal limb patterning pathways in VAD avian limb buds relate to the limb malformations observed in certain retinoid receptor mutants (4) ; the malformed limbs may be the result of marginal retinoid activity during a later period in development. Interestingly, mice knockouts of the RALDH2 gene, an enzyme involved in the generation of RA, do not appear to have limb buds (11) , suggesting species differences.
Using partially vitamin A–depleted rodent models in which the fetuses survive longer and later gestational windows can be examined, it was demonstrated that vitamin A is specifically required during midgestation for fetal lung development and neonatal survival (24 ,42) . Abnormal cell differentiation and diminished expression of elastin gene and a growth-arrest gene were associated with abnormal lung morphology (42) , also seen in mice with deletions in RAR genes (29) . Compound mutants of RAR also exhibit congenital respiratory tract abnormalities (4 ,19) . The importance of adequate maternal/fetal vitamin A nutrition in prevention of neonatal lung injury has been demonstrated clinically and in animal models (28) . Similarly, renal development is affected by retinoids (43) , also noted in the RALDH2 knockout mice (11) ; congenital malformations in the urogenital system are seen in fetuses of RAR compound mutant mice (4) .