38
L. Quadro and E. K. Spiegler
These subjects have been a focus of intense research for the past decade, and will
be discussed in the next section.
Current State of the Field
The turning point in understanding the mechanisms of the maternal-fetal transfer
of retinoids and β-carotene was the development of methods of manipulating the
mouse genome, which allowed the functions of specific genes, proteins and metabolic
pathways to be investigated at the molecular level.
The Retinol-RBP Pathway Is the Primary Contributor
to Embryonic Development
Retinol-RBP is the major circulating form of VA in mammals with a normal VA
status and in the fasting state, (Fig. 2.2). Thus, it was predicted that the retinolRBP pathway would be the main source of retinoids for the developing mammalian
fetus. In agreement with this expectation, inhibition of RBP synthesis in presomitic
and 3- to 12-somite-pair cultured mouse embryos resulted in malformations of the
vitelline vessels, cranial neural tube and eyes, depending upon the stage of embryonic
development at the time of antisense injection (Bavik, Ward, and Chambon 1996).
The generation of the RBP knockout mice (RBP
−/− ), however, countered these conclusions and clearly demonstrated that retinoid transport to the developing embryo
in vivo was much more complex than anticipated (Quadro et al. 1999).
Mice lacking RBP are viable and fertile when maintained on a VA-sufficient
diet [containing no less than 22 IU VA/g of diet (Wassef et al. 2012)], yielding
viable embryos that display only mild and transient cardiac developmental anomalies
(Wendler et al. 2003; Quadro et al. 1999). The absence of phenotypic defects in
RBP
−/− embryos from dams on a VA-sufficient diet clearly suggests the existence
of alternative pathway(s) for VA delivery to the fetus.
Given their inability to efficiently utilize hepatic retinoid stores, RBP
−/− mice
depend on a continuous intake of VA to support normal physiological processes,
including embryogenesis (Quadro et al. 2004a, b, 2005). Indeed, in RBP
−/− dams,
the higher levels of retinyl esters incorporated into chylomicrons and/or VLDL particles constitute a sufficient alternative source of VA to support relatively normal
embryonic development (Quadro et al. 1999, 2004a, b). Upon deprivation of dietary
VA, though, RBP
−/− dams generate embryos with a wide range of VA deficiency
phenotypes, depending upon the period of maternal dietary VA deprivation (i.e., the
degree of maternal VA deficiency) (Quadro et al. 2005). A regimen of severe maternal
VA deprivation was found to cause early embryonic lethality (Quadro et al. 2005).
L. Quadro and E. K. Spiegler
These subjects have been a focus of intense research for the past decade, and will
be discussed in the next section.
Current State of the Field
The turning point in understanding the mechanisms of the maternal-fetal transfer
of retinoids and β-carotene was the development of methods of manipulating the
mouse genome, which allowed the functions of specific genes, proteins and metabolic
pathways to be investigated at the molecular level.
The Retinol-RBP Pathway Is the Primary Contributor
to Embryonic Development
Retinol-RBP is the major circulating form of VA in mammals with a normal VA
status and in the fasting state, (Fig. 2.2). Thus, it was predicted that the retinolRBP pathway would be the main source of retinoids for the developing mammalian
fetus. In agreement with this expectation, inhibition of RBP synthesis in presomitic
and 3- to 12-somite-pair cultured mouse embryos resulted in malformations of the
vitelline vessels, cranial neural tube and eyes, depending upon the stage of embryonic
development at the time of antisense injection (Bavik, Ward, and Chambon 1996).
The generation of the RBP knockout mice (RBP
−/− ), however, countered these conclusions and clearly demonstrated that retinoid transport to the developing embryo
in vivo was much more complex than anticipated (Quadro et al. 1999).
Mice lacking RBP are viable and fertile when maintained on a VA-sufficient
diet [containing no less than 22 IU VA/g of diet (Wassef et al. 2012)], yielding
viable embryos that display only mild and transient cardiac developmental anomalies
(Wendler et al. 2003; Quadro et al. 1999). The absence of phenotypic defects in
RBP
−/− embryos from dams on a VA-sufficient diet clearly suggests the existence
of alternative pathway(s) for VA delivery to the fetus.
Given their inability to efficiently utilize hepatic retinoid stores, RBP
−/− mice
depend on a continuous intake of VA to support normal physiological processes,
including embryogenesis (Quadro et al. 2004a, b, 2005). Indeed, in RBP
−/− dams,
the higher levels of retinyl esters incorporated into chylomicrons and/or VLDL particles constitute a sufficient alternative source of VA to support relatively normal
embryonic development (Quadro et al. 1999, 2004a, b). Upon deprivation of dietary
VA, though, RBP
−/− dams generate embryos with a wide range of VA deficiency
phenotypes, depending upon the period of maternal dietary VA deprivation (i.e., the
degree of maternal VA deficiency) (Quadro et al. 2005). A regimen of severe maternal
VA deprivation was found to cause early embryonic lethality (Quadro et al. 2005).