2 Maternal-Fetal Transfer of Vitamin A …
29
Introduction
The placenta is a hallmark of mammalian embryonic development. It is a transient
organ that develops during pregnancy to enable the efficient exchange of gas, nutrients
and embryonic wastes between the mother and fetus (Rai and Cross 2014; Watson
and Cross 2005). Despite morphological and histological differences in the placenta
among mammalian species, the above-mentioned function is always fulfilled by the
establishment of a blood-placenta barrier. This barrier enables the juxtaposition of
the fetal blood vessels to the maternal blood network, facilitating the transfer of
nutrients and gas without direct contact of the maternal and fetal circulations (Rai
and Cross 2014; Watson and Cross 2005). In the disk-shaped hemochorial placenta of
humans and rodents, the blood-placental barrier consists of fetal vascular endothelial
cells and three types of trophoblast cells. A single fenestrated layer of sinusoidal
trophoblast giant cells faces the maternal blood sinuses on one side, and a double
layer of syncytiotrophoblast (SynT) cells on the other side. Of these, SynT layer II
is adjacent to the fetal blood vessels (Nadeau and Charron 2014). Each SynT layer
forms, by cell fusion, a postmitotic multinucleated syncytium that fulfills transport
functions while physically separating the maternal and fetal circulation (Nadeau and
Charron 2014; Fig. 2.1). Thus, complex molecular mechanisms are needed to enable
the movement of nutrients across the various cell layers.
The essential nutrient (VA) is critical to ensure proper embryonic development
as it supports vital processes such as cell fate specification, patterning and differentiation (Clagett-Dame and Knutson 2011). Embryonic VA deficiency or excess
have long been linked to congenital malformations in humans and experimental animal models, mainly owing to the defective transcriptional action of retinoic acid
(RA), the active form of VA, during embryogenesis. RA, predominantly synthesized within embryonic tissues from preformed VA (mainly retinol), serves as the
ligand of the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) (Al
Tanoury et al. 2013). These transcription factors regulate the expression of a number of genes that are important in development (Paschaki et al. 2013) in a spatial
and temporal manner that influences the pattern formation of essentially all organs
(Rhinn and Dolle 2012). The embryo is unable to synthesize retinoids (VA and its
derivatives, including RA), and is strongly dependent upon the maternal delivery
of retinoids through transplacental transfer. The most abundant retinoids available
to the developing embryo from the maternal bloodstream are retinol bound to its
specific carrier, retinol-binding protein (RBP or RBP4); retinyl esters (RE); and proVA carotenoids (mainly β-carotene) that are incorporated into chylomicrons and
lipoproteins (Spiegler et al. 2012; Fig. 2.2).
This chapter focuses on the physiological and molecular mechanisms of retinoid
and pro-retinoid transfer from mother to fetus across the placenta and the impacts
of retinoids on mammalian embryonic development. Prior to the establishment of
the functional placenta (at 10.5 days post coitum, dpc, in mice (Rossant and Cross
2001; Cross 2006)), another transient organ, the yolk sac, enables the exchange of
29
Introduction
The placenta is a hallmark of mammalian embryonic development. It is a transient
organ that develops during pregnancy to enable the efficient exchange of gas, nutrients
and embryonic wastes between the mother and fetus (Rai and Cross 2014; Watson
and Cross 2005). Despite morphological and histological differences in the placenta
among mammalian species, the above-mentioned function is always fulfilled by the
establishment of a blood-placenta barrier. This barrier enables the juxtaposition of
the fetal blood vessels to the maternal blood network, facilitating the transfer of
nutrients and gas without direct contact of the maternal and fetal circulations (Rai
and Cross 2014; Watson and Cross 2005). In the disk-shaped hemochorial placenta of
humans and rodents, the blood-placental barrier consists of fetal vascular endothelial
cells and three types of trophoblast cells. A single fenestrated layer of sinusoidal
trophoblast giant cells faces the maternal blood sinuses on one side, and a double
layer of syncytiotrophoblast (SynT) cells on the other side. Of these, SynT layer II
is adjacent to the fetal blood vessels (Nadeau and Charron 2014). Each SynT layer
forms, by cell fusion, a postmitotic multinucleated syncytium that fulfills transport
functions while physically separating the maternal and fetal circulation (Nadeau and
Charron 2014; Fig. 2.1). Thus, complex molecular mechanisms are needed to enable
the movement of nutrients across the various cell layers.
The essential nutrient (VA) is critical to ensure proper embryonic development
as it supports vital processes such as cell fate specification, patterning and differentiation (Clagett-Dame and Knutson 2011). Embryonic VA deficiency or excess
have long been linked to congenital malformations in humans and experimental animal models, mainly owing to the defective transcriptional action of retinoic acid
(RA), the active form of VA, during embryogenesis. RA, predominantly synthesized within embryonic tissues from preformed VA (mainly retinol), serves as the
ligand of the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) (Al
Tanoury et al. 2013). These transcription factors regulate the expression of a number of genes that are important in development (Paschaki et al. 2013) in a spatial
and temporal manner that influences the pattern formation of essentially all organs
(Rhinn and Dolle 2012). The embryo is unable to synthesize retinoids (VA and its
derivatives, including RA), and is strongly dependent upon the maternal delivery
of retinoids through transplacental transfer. The most abundant retinoids available
to the developing embryo from the maternal bloodstream are retinol bound to its
specific carrier, retinol-binding protein (RBP or RBP4); retinyl esters (RE); and proVA carotenoids (mainly β-carotene) that are incorporated into chylomicrons and
lipoproteins (Spiegler et al. 2012; Fig. 2.2).
This chapter focuses on the physiological and molecular mechanisms of retinoid
and pro-retinoid transfer from mother to fetus across the placenta and the impacts
of retinoids on mammalian embryonic development. Prior to the establishment of
the functional placenta (at 10.5 days post coitum, dpc, in mice (Rossant and Cross
2001; Cross 2006)), another transient organ, the yolk sac, enables the exchange of