Endocrinology Vol. 139, No. 3 847-851
Copyright © 1998 by The Endocrine Society
Analysis of Vitamin D-Dependent Calcium-Binding Protein Messenger Ribonucleic Acid Expression in Mice Lacking the Vitamin D Receptor1
Yan Chun Li2,
Alison E. Pirro and
Marie B. Demay
Endocrine Unit, Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Marie B. Demay, M.D., Endocrine Unit, Wellman 501, Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts 02114.
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Abstract
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To investigate the roles of the receptor-dependent actions of
1,25-dihydroxyvitamin D3
[1,25-(OH)2D3] in the regulation of vitamin
D-dependent calcium-binding proteins (calbindin-D), the messenger RNA
(mRNA) levels of calbindin-D9k and -28k were examined in vitamin D
receptor (VDR)-ablated mice and control littermates. In VDR-ablated
mice, calbindin-D9k mRNA was dramatically reduced in the intestine,
kidneys, lungs, and brain; however, calbindin-D28k mRNA was only
moderately decreased in the kidney. After
1,25-(OH)2D3 injection, calbindin-D9k mRNA
levels and renal and alveolar calbindin-D28k mRNA levels were induced
in control animals, but not in the homozygous mice.
When the mice were fed a diet high in lactose, calcium, and phosphorus,
intestinal calbindin-D9k mRNA levels in the homozygous mice were
restored to those in their control littermates. However, this diet
failed to normalize extraintestinal calbindin mRNA levels.
These findings demonstrate that the receptor-dependent actions of
1,25-(OH)2D3 regulate calbindin-D9k gene
expression and that tissue-specific factors modulate the effects of
1,25-(OH)2D3 on calbindin-D28k gene expression.
These data also demonstrate that in the absence of a functional VDR, a
high local concentration of calcium, phosphorus, and/or lactose in the
intestinal lumen can normalize intestinal calbindin-D9k mRNA levels.
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Introduction
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VITAMIN D-dependent calcium-binding
proteins (calbindin-D) are the major proteins thought to be
involved in intracellular calcium transport in the intestine and the
kidneys (1). Two classes of calbindin-D have been described in mammals:
the 9,000-dalton calbindin (calbindin-D9k) and the 28,000-dalton
calbindin (calbindin-D28k). Only calbindin-D28k is found in avian
species (2). First identified in the intestine (3, 4, 5), calbindin-D9k is
also expressed in the kidneys (6, 7), the placenta, the yolk sac
(8, 9, 10), and the lungs (11). Calbindin-D28k is highly expressed in
avian intestine (12, 13) and in avian and mammalian kidneys (6, 7, 14, 15, 16). It is also found in other tissues, including the brain
(17, 18, 19), the pancreas (20, 21, 22), and chicken egg shell gland (23). The
expression of calbindin-D9k and calbindin-D28k in the intestine and
kidneys has been shown to be regulated by 1,25-dihydroxyvitamin
D3 [1,25-(OH)2D3] in animal
models as well as in cell and organ cultures (24, 25, 26, 27, 28, 29, 30). A vitamin D
response element has been identified in both the rat calbindin-D9k (31)
and the mouse calbindin-D28k (32) gene promoters. Although attempts to
find such an element in the chicken calbindin-D28k promoter have been
unsuccessful (33, 34), experiments using
1,25-(OH)2D3 analogs in chicks demonstrate a
correlation between 1,25-(OH)2D3 receptor
binding and the induction of intestinal calbindin-D28k messenger RNA
(mRNA) (35), suggesting that the genomic actions of
1,25-(OH)2D3 play a key role in the regulation
of this gene. The regulation of calbindin-D9k and -28k by
1,25-(OH)2D3 has been thought to involve both
transcriptional and posttranscriptional mechanisms (27, 36, 37). In
other tissues, including the brain, the placenta, and the lungs,
however, calbindin-D genes have not been shown to be regulated by
1,25-(OH)2D3 (11, 25, 38), suggesting that
regulation of calbindin-D gene expression by
1,25-(OH)2D3 involves tissue-specific
factors.
Calcium has also been found to modulate the actions of
1,25-(OH)2D3 on calbindin gene expression.
In vitro experiments demonstrate that the induction of renal
calbindin-D28k by 1,25-(OH)2D3 is enhanced by
high levels of extracellular calcium (39). In rat duodenal organ
cultures, calcium alone is able to stimulate calbindin-D9k mRNA
synthesis (28). In chicks and rats, however, intestinal calbindin-D28k
and -9k expression is induced by a low calcium diet and inhibited by a
high calcium diet (40, 41). The molecular basis for the discrepancy
between the in vitro and in vivo findings remains
to be elucidated.
Although studies in vitamin D-deficient animals have contributed
significantly to our understanding of calbindin-D gene expression,
they have not distinguished the effects of hypocalcemia from those of
vitamin D deficiency. To further clarify the relative contributions of
the receptor-dependent actions of 1,25-(OH)2D3
and serum calcium to calbindin-D gene expression, we examined
calbindin-D mRNA levels in the intestine, kidneys, brain, and lungs of
mice with targeted ablation of the vitamin D receptor (VDR) on a normal
diet as well as on a high lactose, high calcium, high phosphorus diet.
The later dietary treatment normalized random blood ionized calcium in
the VDR-ablated mice.
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Materials and Methods
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Animal maintenance
VDR null mice (42) and control mice were maintained in a virus-
and parasite-free barrier facility and exposed to a 12-h light, 12-h
dark cycle. The animals were fed autoclaved Purina rodent chow (5010,
Ralston Purina, St. Louis, MO) containing 1% calcium, 0.67%
phosphorus, 0% lactose, and 4.4 IU vitamin D/g. The 
-irradiated
test diet (TD96348, Teklad, Madison, WI), containing 2% calcium,
1.25% phosphorus, and 20% lactose supplemented with 2.2 IU vitamin
D/g, was begun at 19 days of age. For vitamin D treatment, 15 h
before death, the animals were injected ip with 10 pmol
1,25-(OH)2D3 in propylene glycol. Serum ionized
calcium determinations were performed using a Ciba/Corning
Ca2+/pH analyzer.
RNA isolation
Mice were exsanguinated under anesthesia, and the brain,
kidneys, duodenum, and lungs were removed immediately and placed into
Trizol solution (Life Technologies, Bethesda, MD). The tissues were
homogenized immediately using a Polytron (Brinkmann Instruments,
Westbury, NY). Total RNA was isolated according to the Trizol
manufacturer’s instructions. RNA samples isolated from wild-type or
heterozygous littermates were used as controls.
Northern blot analysis
Total RNA (25 µg) was denatured and separated in a 1.2%
agarose gel containing 0.6 M formaldehyde as previously
described (43). The RNA was transferred onto a Nylon 66 plus membrane
(Pharmacia Biotech, San Francisco, CA) in 20 x SSC (standard
saline citrate). The membrane was baked at 80 C for 2 h and
hybridized with a complementary DNA (cDNA) probe labeled with
[
-32P]deoxy-ATP (New England Nuclear, Boston, MA)
using a Random Primed Labeling kit (Boehringer Mannheim, Indianapolis,
IN) or with a -32P-labeled antisense oligonucleotide
probe for 18S ribosomal RNA. The cDNA probes used were a 340-bp
BamHI-PvuII fragment and a 1.2-kilobase
BamHI-PvuII fragment of mouse calbindin-D9k and
-28k cDNA, respectively (gifts from Dr. Sylvia Christakos, University
of Medicine and Dentistry of New Jersey, Newark, NJ). Hybridization was
carried out at 42 C in a solution containing 50% formamide, 6 x
SSPE (1 x SPPE = 180 mM NaCl, 10 mM
NaH2PO4, 1 mM EDTA, pH 7.4), 5
x Denhardt’s solution, 0.5% SDS, and 100 µg/ml denatured salmon
sperm DNA. After hybridization, the membranes were exposed to x-ray
films (Eastman Kodak, Rochester, NY) at -80 C for autoradiography. The
relative amount of mRNA was assessed by densitometric scanning of
autoradiograms. ß-Actin and 18S ribosomal RNA signals were used to
normalize for variations in RNA loading.
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Results
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The expression of calbindin-D9k and -28k mRNAs was examined in
control and VDR-ablated mouse littermates. As shown in Fig. 1A
, in the duodenum, calbindin-D9k mRNA
levels were markedly reduced in the homozygous mice at 2, 5, and 11
weeks of age (6.4 ± 1.6-fold reduction by 11 weeks). The mRNA
levels of the heterozygotes were identical to those of the wild-type
littermates (data not shown), consistent with their normal phenotype
(42). As reported previously (24, 25), calbindin-D28k mRNA was
undetectable in the intestine of mice from all three groups. The
expression of calbindin-D9k and 28k mRNAs in the kidney was also
examined (Fig. 1B). Although calbindin-D9k mRNA was barely detectable
in homozygous mice at 2, 5, and 11 weeks of age, the level of
calbindin-D28k mRNA was only moderately reduced (1.32 ± 0.02-fold
reduction by 11 weeks, based on the smallest mRNA species). Consistent
with previous reports, three calbindin-D28k mRNA species were present
in the kidney (25, 37). Both calbindin-D9k and -28k mRNA levels of the
heterozygous mice were identical to those of their wild-type
littermates (not shown). In the brain, calbindin-D9k mRNA
expression was detected in the wild-type and heterozygous mice and was
drastically reduced in the homozygous littermates (Fig. 1C). However,
brain calbindin-D28k mRNA levels in the homozygotes were identical to
those of the wild-type and heterozygous littermates (Fig. 1C). In the
lungs, calbindin-D9k mRNA was reduced in the homozygous mice (2.1
± 0.3-fold reduction), whereas calbindin-D28k mRNA levels were not
affected (Fig. 1D).
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Figure 1. Calbindin-D mRNA expression in VDR knock-out mice.
Total RNA was isolated from mouse littermates of different age groups
as indicated. Twenty-five micrograms of total RNA per lane were used
for Northern blot analysis. The membrane was sequentially hybridized
with mouse calbindin-D9k, calbindin-D28k, and ß-actin cDNA probes.
ß-Actin mRNA serves as an internal control for RNA loading. +/+, Wild
type; +/-, heterozygote; -/-, homozygote; CaBP-D, calbindin-D. A,
Calbindin-D mRNA expression in the intestine. Total RNA was isolated
from the duodenum of 2-, 5-, and 11-week-old littermates and subjected
to Northern analysis. B, Calbindin-D mRNA expression in the kidney.
Total RNA, used for Northern analysis, was isolated from the kidneys of
2-, 5-, and 11-week-old littermates as indicated. C, Calbindin-D mRNA
expression in the brain. Total RNA was isolated from the whole brain of
5-week-old littermates. D, Calbindin-D mRNA expression in the lung.
Total RNA was isolated from lungs of the 11-week-old littermates.
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To further evaluate the effects of receptor-dependent actions of
1,25-(OH)2D3 on calbindin-D gene expression,
1,25-(OH)2D3 was injected into VDR-ablated and
heterozygous littermates at 11 weeks of age, and RNA was isolated from
the intestine, kidneys, brain, and lungs 15 h later. This time
point was chosen because previous reports showed that both
calbindin-D9k and -28k mRNAs were induced in this time frame in vitamin
D-deficient animals (24, 25). As shown in Fig. 2, in the heterozygous mice,
calbindin-D9k mRNA levels were induced 2.1 ± 0.14-fold in the
intestine (Fig. 2A), 1.8 ± 0.02-fold in the kidneys (Fig. 2B),
and 1.7 ± 0.06-fold in the lungs (Fig. 2D) in response to
1,25-(OH)2D3, but calbindin-D9k levels were not
changed by 1,25-(OH)2D3 treatment in the
homozygous receptor-ablated mice (Fig. 2). Calbindin-D28k mRNA
expression was also induced by 1,25-(OH)2D3 in
the kidneys (1.3 ± 0.16-fold induction; Fig. 2B) and lungs
(1.79 ± 0.31-fold induction; Fig. 2D) of the heterozygous mice,
but not in those of the homozygous mice. In the brain, calbindin-D28k
mRNA was unchanged by 1,25-(OH)2D3 treatment
(Fig. 2C).
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Figure 2. Induction of calbindin-D mRNA by
1,25-(OH)2D3. Mouse littermates (9 weeks old)
were injected ip with 10 pmol
1,25-(OH)2D3/mouse and killed 15 h later
for RNA isolation. Twenty-five micrograms of total RNA isolated from
the intestine (A), kidneys (B), brain (C), and lungs (D) were used for
Northern blot analysis. The membrane was sequentially hybridized with
calbindin-D9k, calbindin-D28k, and ß-actin cDNA probes. +/-,
Heterozygote; -/-, homozygote; CaBP-D, calbindin-D; +D, mouse
injected with 1,25-(OH)2D3 as described in
Materials and Methods.
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To examine the effects of calcium and phosphorus on calbindin-D gene
expression in the absence of the genomic actions of
1,25-(OH)2D3, the mice were fed a diet high in
lactose, calcium, and phosphorus. As shown in Fig. 3, this diet normalized intestinal
calbindin-D9k mRNA expression in 5-week-old VDR-ablated mice (Fig. 3A).
Similar results were obtained in 11-week-old littermates (data not
shown). However, renal (Fig. 3B) and brain (not shown) calbindin-D9k
mRNA levels in the homozygous mice failed to normalize, as did renal
calbindin-D28k mRNA levels (Fig. 3B).
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Figure 3. Effects of dietary calcium, phosphorus, and/or
lactose on calbindin-D mRNA expression. Mice were fed the TD96348 diet
as described in Materials and Methods. Total RNA was
isolated from the duodenum and kidneys of 5-week-old littermates.
Twenty-five micrograms of total RNA were used in each lane. The
membrane was hybridized sequentially with calbindin-D9k,
calbindin-D28k, and ß-actin cDNA probes or an antisense
oligonucleotide probe of 18S ribosomal RNA. +/+, Wildtype; -/-,
homozygote; CaBP-D, calbindin-D. A, Calbindin-D9k mRNA expression in
the intestine. B, Calbindin-D9k and 28k mRNA expression in the
kidney.
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Discussion
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In vivo studies of the receptor-dependent actions of
1,25-(OH)2D3 on calbindin-D gene expression
have been complicated by the inability to differentiate the effects of
hormone deficiency from those of hypocalcemia. The model we have used,
an in vivo model of VDR deficiency, allows a more precise
evaluation of the genomic effects of
1,25-(OH)2D3 on target gene expression. The
effects of VDR ablation on calbindin-D9k and 28k mRNA levels are
summarized in Table 1.
Consistent with observations in vitamin D-deficient animals,
calbindin-D9k mRNA levels were dramatically reduced in the kidney and
intestine of the receptor-ablated mice. It is of interest, however,
that unlike observations in murine models of vitamin D deficiency (11),
calbindin-D9k levels were reduced in the lungs and the brain as well.
Treatment of control littermates with
1,25-(OH)2D3 induced calbindin-D9k mRNA in all
tissues examined, confirming that calbindin-D9k gene expression is
regulated by 1,25-(OH)2D3 in these tissues. A
reduction of calbindin-D9k expression in the intestine and
kidney was observed in normocalce-mic 2-week-old VDR-ablated mice
(42), suggesting that it was a consequence of receptor deficiency
rather than hypocalcemia.
Although vitamin D response elements have been found in both the murine
calbindin-D9k and -28k genes (31, 32), our studies demonstrate that the
VDR dependence of calbindin-D28k gene expression varies among the
tissues examined. Consistent with the observation that the kidney and
lungs express the VDR, calbindin-D28k mRNA levels in these tissues
were induced in the control mice treated with
1,25-(OH)2D3. However, renal calbindin-D28k
mRNA levels were moderately reduced, and alveolar calbindin-D28k
expression was not affected by ablation of the VDR. These findings
confirm the previous observation that a portion of renal calbindin-D28k
expression is constitutive (44). The expression of calbindin-D28k in
the lungs is a novel finding, and our data suggest that its basal
expression is constitutive, although mRNA levels are induced by
1,25-(OH)2D3 treatment. In the brain, however,
calbindin-D28K mRNA expression is largely restricted to the Purkinjie
cells of the cerebellum, which do not express the VDR (2). Consistent
with this observation, calbindin-D28K levels were not affected by VDR
status, nor were they modulated by 1,25-(OH)2D3
treatment in control littermates.
The observation that a high lactose, high calcium, high phosphorus diet
is able to normalize intestinal calbindin-D9k expression in the
VDR-ablated mice supports the hypothesis that multiple factors interact
to regulate expression of this gene in the enterocyte. The calcium,
lactose, and phosphorus concentrations of this test diet are higher
than those in regular lab chow and murine milk (45), suggesting that
the high local concentration of one or more of these components is
responsible for normalizing intestinal calbindin-D9K mRNA levels in the
VDR-ablated mice by inducing either gene expression or mRNA stability.
Although normalization of intestinal calbindin 9K mRNA levels results
in normal random ionized calcium levels in VDR-ablated mice, studies of
intestinal calcium absorption will be required to confirm that the
defect in intestinal calcium transport in VDR-ablated mice is corrected
along with the calbindin-D9k mRNA levels.
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Footnotes
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1 This work was supported by NIH Grant DK-46974 (to M.B.D.). 
2 NIH fellowship recipient.
Received September 10, 1997.
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Top
Abstract
Introduction
