10
M. A. Asson-Batres
would bind retinol or retinoic acid and form a complex that would (2) interact with
the nucleus to (3) alter gene expression (Takase et al. 1979).
Ultimately, genetic approaches carried out by investigators in two independent
laboratories identified nuclear retinoic acid receptors (RARs/RXRs) (Petkovich et al.
1987; Giguere et al. 1987) that subsequently were shown to mediate the downstream
effects of vitamin A on gene and, consequently, RNA and protein expression (Benbrook et al. 2014). This ground-breaking work and the molecular techniques that
made it possible opened new opportunities to validate and extend the eighty years of
findings that had been generated using the dietary vitamin A deficiency experimental
model.
Current State of the Field
Post 1987
With development of technology that made it possible to localize and target gene
expression, much vitamin A research after the discovery of the RARs was aimed at
unraveling the molecular mechanism(s) for the developmental anomalies previously
observed in vitamin A-deficient embryos. Results from experiments designed to
block vitamin A signaling showed that knocking out nuclear receptors or key enzymes
in the retinoic acid biosynthetic pathway produced effects that were similar to those
produced by removal of vitamin A from the diets of quail, rats, and mice (Zile 2001).
Largely due to a redundancy in receptor and enzyme sub-types, however, inactivating
or overexpressing a single gene in the vitamin A signaling pathway was insufficient
to explain the full extent of the syndrome induced by dietary vitamin A deficiency.
Currently, researchers utilize a combination of molecular, biochemical, and physiological approaches on whole animals and cell and tissue culture systems to discover
and validate mechanisms of action (Niederreither and Dolle 2008). The dietary deficiency experimental model continues to be an important part of the experimental
arsenal used to explore the basis for vitamin A’s role in embryonic and fetal development, including development of the nervous (Maden et al. 1996; White et al. 1998;
Lloret-Vilaspasa et al. 2010; See et al. 2008; Weston et al. 2003), skeletal (Weston
et al. 2003; See et al. 2008), kidney (Batourina et al. 2001), and pancreas systems
(Matthews et al. 2004; Chien et al. 2016).
Vitamin A Deficiency in Postnatal Animals
As a new investigator in the early 1990s, I became intrigued with Walbach and
Howe’s observation that adult rats deficient in vitamin A appeared to be anoxic
(Wolbach and Howe 1925). Because it had been shown that retinoic acid could induce
M. A. Asson-Batres
would bind retinol or retinoic acid and form a complex that would (2) interact with
the nucleus to (3) alter gene expression (Takase et al. 1979).
Ultimately, genetic approaches carried out by investigators in two independent
laboratories identified nuclear retinoic acid receptors (RARs/RXRs) (Petkovich et al.
1987; Giguere et al. 1987) that subsequently were shown to mediate the downstream
effects of vitamin A on gene and, consequently, RNA and protein expression (Benbrook et al. 2014). This ground-breaking work and the molecular techniques that
made it possible opened new opportunities to validate and extend the eighty years of
findings that had been generated using the dietary vitamin A deficiency experimental
model.
Current State of the Field
Post 1987
With development of technology that made it possible to localize and target gene
expression, much vitamin A research after the discovery of the RARs was aimed at
unraveling the molecular mechanism(s) for the developmental anomalies previously
observed in vitamin A-deficient embryos. Results from experiments designed to
block vitamin A signaling showed that knocking out nuclear receptors or key enzymes
in the retinoic acid biosynthetic pathway produced effects that were similar to those
produced by removal of vitamin A from the diets of quail, rats, and mice (Zile 2001).
Largely due to a redundancy in receptor and enzyme sub-types, however, inactivating
or overexpressing a single gene in the vitamin A signaling pathway was insufficient
to explain the full extent of the syndrome induced by dietary vitamin A deficiency.
Currently, researchers utilize a combination of molecular, biochemical, and physiological approaches on whole animals and cell and tissue culture systems to discover
and validate mechanisms of action (Niederreither and Dolle 2008). The dietary deficiency experimental model continues to be an important part of the experimental
arsenal used to explore the basis for vitamin A’s role in embryonic and fetal development, including development of the nervous (Maden et al. 1996; White et al. 1998;
Lloret-Vilaspasa et al. 2010; See et al. 2008; Weston et al. 2003), skeletal (Weston
et al. 2003; See et al. 2008), kidney (Batourina et al. 2001), and pancreas systems
(Matthews et al. 2004; Chien et al. 2016).
Vitamin A Deficiency in Postnatal Animals
As a new investigator in the early 1990s, I became intrigued with Walbach and
Howe’s observation that adult rats deficient in vitamin A appeared to be anoxic
(Wolbach and Howe 1925). Because it had been shown that retinoic acid could induce