1 How Dietary Deficiency Studies Have Illuminated the Many Roles …
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The results showed that the number of proliferating cell nuclear antigen (PCNA)
positive cell profiles per mm was an average of fivefold higher in vitamin A deficient
sensory epithelia than it was in the tissues of age-matched, vitamin A sufficient
control rats. This is an interesting finding because it is counter to evidence showing
that the number of proliferating progenitors in the normal postnatal rodent sensory
epithelium declines with rat age (Weiler and Farbman 1997, 1998a, b). In fact, the
increased numbers of PCNA positive cells we observed in vitamin A deficient sensory
epithelia are more in line with the mean densities of progenitors normally found in
vitamin A sufficient olfactory epithelia from rats that are barely beyond the stage
of weaning (Weiler and Farbman 1998a, b) (postnatal day 21; Weiler and Farbman
1997). These data support the conclusion that cell proliferation is upregulated by
vitamin A deficiency in the postnatal rodent olfactory epithelium (Asson-Batres
et al. 2003a, b).
In contrast, there was a visible decrease in the number of OMP positive cell
profiles in vitamin A deficient tissue relative to vitamin A sufficient controls (AssonBatres 2003b). We also observed a relative decrease in adenylate cyclase (another
antibody marker for mature olfactory neurons) labeled cells in vitamin A deficient
olfactory epithelia (Fig. 1.4, Asson-Batres, unpublished), which supports the idea
that the decreased number of OMP positive cell profiles is not due to a specific
loss of OMP expression, but rather to a depletion in the number of mature olfactory
receptor neurons (ORNs) in the postnatal rodent sensory epithelium.
Taken together, our results support the idea that vitamin A regulates progenitor
cell proliferation and is required for the production and/or maintenance of terminally
differentiated ORNs in vivo. These in vivo findings mirror those observed using
in vitro model systems which show that retinoic acid inhibits stem cell proliferation
and induces differentiation along a neural pathway (Janesick et al. 2015). More
recently, other laboratories have used vitamin A deficiency experimental models to
study retinoic acid effects on the brain, and results from these studies indicate that
vitamin A is also an important regulator of neurogenesis in the central nervous system
before and after birth (White et al. 2000; Jacobs et al. 2006; Bonnet et al. 2008). The
mechanisms for effects of vitamin A/retinoic acid on progenitor proliferation, neuron
differentiation, maturation, lifespan, and/or turnover in the olfactory system remain
unresolved, but studies using molecular and genetic approaches support the idea that
retinoid signaling operates at multiple steps in the olfactory pathway to support its
development and maintenance throughout life (Paschaki et al. 2013; Login et al.
2015; Hagglund et al. 2006; Oztokatli et al. 2012; Rochette-Egly 2015).
The Hippocampus—Synaptic Plasticity
Learning and memory are higher order functions of the mammalian brain that
are thought to be mediated by hippocampal “synaptic plasticity”, that is, dynamic
changes in the wiring and firing of neurons located in the postnatal hippocampus.
Vitamin A deficiency studies, in combination with genetic inactivation models, have
15
The results showed that the number of proliferating cell nuclear antigen (PCNA)
positive cell profiles per mm was an average of fivefold higher in vitamin A deficient
sensory epithelia than it was in the tissues of age-matched, vitamin A sufficient
control rats. This is an interesting finding because it is counter to evidence showing
that the number of proliferating progenitors in the normal postnatal rodent sensory
epithelium declines with rat age (Weiler and Farbman 1997, 1998a, b). In fact, the
increased numbers of PCNA positive cells we observed in vitamin A deficient sensory
epithelia are more in line with the mean densities of progenitors normally found in
vitamin A sufficient olfactory epithelia from rats that are barely beyond the stage
of weaning (Weiler and Farbman 1998a, b) (postnatal day 21; Weiler and Farbman
1997). These data support the conclusion that cell proliferation is upregulated by
vitamin A deficiency in the postnatal rodent olfactory epithelium (Asson-Batres
et al. 2003a, b).
In contrast, there was a visible decrease in the number of OMP positive cell
profiles in vitamin A deficient tissue relative to vitamin A sufficient controls (AssonBatres 2003b). We also observed a relative decrease in adenylate cyclase (another
antibody marker for mature olfactory neurons) labeled cells in vitamin A deficient
olfactory epithelia (Fig. 1.4, Asson-Batres, unpublished), which supports the idea
that the decreased number of OMP positive cell profiles is not due to a specific
loss of OMP expression, but rather to a depletion in the number of mature olfactory
receptor neurons (ORNs) in the postnatal rodent sensory epithelium.
Taken together, our results support the idea that vitamin A regulates progenitor
cell proliferation and is required for the production and/or maintenance of terminally
differentiated ORNs in vivo. These in vivo findings mirror those observed using
in vitro model systems which show that retinoic acid inhibits stem cell proliferation
and induces differentiation along a neural pathway (Janesick et al. 2015). More
recently, other laboratories have used vitamin A deficiency experimental models to
study retinoic acid effects on the brain, and results from these studies indicate that
vitamin A is also an important regulator of neurogenesis in the central nervous system
before and after birth (White et al. 2000; Jacobs et al. 2006; Bonnet et al. 2008). The
mechanisms for effects of vitamin A/retinoic acid on progenitor proliferation, neuron
differentiation, maturation, lifespan, and/or turnover in the olfactory system remain
unresolved, but studies using molecular and genetic approaches support the idea that
retinoid signaling operates at multiple steps in the olfactory pathway to support its
development and maintenance throughout life (Paschaki et al. 2013; Login et al.
2015; Hagglund et al. 2006; Oztokatli et al. 2012; Rochette-Egly 2015).
The Hippocampus—Synaptic Plasticity
Learning and memory are higher order functions of the mammalian brain that
are thought to be mediated by hippocampal “synaptic plasticity”, that is, dynamic
changes in the wiring and firing of neurons located in the postnatal hippocampus.
Vitamin A deficiency studies, in combination with genetic inactivation models, have