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The Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen, AB21 9SB, Scotland
4To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • rats • pregnancy • fetal growth • growth arrest • apoptosis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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,
Hales and Barker 1992
). A number of animal studies have
shown that the early periods of fetal growth are particularly sensitive
to the nutritional status of the mother (Davison and Dobbing
1996
, Widdowson and McCance 1963
). Once growth
has been perturbed, the fetus never fully recovers and continues to
grow more slowly. Furthermore, an animal undernourished in utero does
not develop symmetrically. For example, feeding pregnant rats a
low-protein diet produces a modest decrease in the birth weight of
the pups, but as a proportion of the whole body weight, the kidneys are
more severely affected than the heart (Rees et al. 1999
). Protein deficiency also affects the ultrastructure of
organs including the kidney, liver and pancreas (Desai et al. 1995
, Snoeck et al. 1990
).
Little is known about the mechanisms that cause this asymmetric growth
and development. Rat embryos up to d 11.5 of gestation can be
successfully cultured in vitro, with growth rates that are close to
those found in vivo, in a simple medium containing essential nutrients
and serum (New 1978
). These experiments show that the
fetus and its placenta are largely autonomous and do not require
positive growth factors from the mother (Alsat et al. 1995
). There is also evidence that cells derived from the fetus
have negative controls that respond to the availability of nutrients in
the medium and suppress growth. This is not a passive process; growth
arrest causes specific increases in mRNAs that are normally only found
at low levels in exponentially dividing cells. Despite extensive study
of cell cultures, there is little information on the role of these
genes during fetal development.
Among the genes upregulated in response to nutrient stress in cell
cultures are the growth arrest and DNA damage
(GADD)5
(Fornace et al. 1989
) and the growth arrest specific
(GAS) genes (Schneider et al. 1988
). Their expression is
sensitive to a variety of nutrients, including amino acids
(Fleming et al. 1998
, Marten et al. 1994
), nucleotides (Linke et al. 1996
) or
glucose (Carlson et al. 1993
). The GADD and GAS genes
code for a diverse range of proteins with a variety of functions,
including the suppression of DNA synthesis (Ruaro et al. 1997
, Smith et al. 1994
), the inhibition of
differentiation (Batchvarova et al. 1995
) and the
induction of apoptosis (Brancollini et al. 1995
,
Fabbretti et al. 1995
, Goruppi et al. 1996
). The response of some genes is rapid but transient, with
expression reaching its maximum within 24 h, whereas others
respond more slowly over several d (Fleming et al. 1998
). Other stimuli, such as DNA damage or contact inhibition,
also increase gene expression. There is evidence for the involvement of
the tumor suppressor p53 (Linke et al. 1996
) and the
transcriptional activator C/EBP-ß (Smith et al. 1994
)
in these processes.
Previous reports have shown that the GAS and GADD genes are expressed
during the development of several tissues (Coccia et al. 1992
, Manfioletti et al. 1993
, Nakano et al. 1996
). This observation suggests that these genes may play
a part in the negative control of fetal growth. To characterize their
expression during the development of the rat fetus, we have measured
the levels of the GAS and GADD gene mRNAs in the placenta, heart and
kidneys. These three structures are formed at different stages in
development: the placenta is the earliest to appear followed by the
heart and finally the kidneys (Wilson and Warkany 1949
).
Our data show that the GAS and GADD genes are not expressed uniformly
during the formation of these three organs. This change in the negative
controls during development may be a possible mechanism mediating the
effects of maternal under-nutrition on fetal development.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Female rats from the Rowett Hooded Lister strain were fed normal stock CRM diet (Proximate analysis: protein, 17.9%; crude oil, 2.4%; carbohydrate, 57%; fiber, 3.6%; digestible energy, 13.3 MJ/kg. Supplied by SDS, Witham, Essex, UK). Animals of ~230 g body weight were caged overnight with normal males, and mating was confirmed on the following morning by the presence of a plug (d 0.5). Rats were killed at different points during pregnancy; the placentas were separated from the fetuses, which were dissected; and the organs were frozen immediately in liquid nitrogen. All experimental procedures were approved and conducted in accordance with the UK Animals (Scientific Procedures) Act, 1986.
RNA extraction.
Frozen tissue samples were transferred directly to Tri-reagent (Sigma, Poole, Dorset, UK) using ~1 mL per 100 mg of tissue. The samples were then disrupted by homogenization for 10 s with an Ultra-Turrax homogenizer (Janke & Kunkel, Staufer, Germany) at maximum speed (24,000 rpm). RNA was prepared from this mixture according to the manufacturers instructions.
cDNA probes.
Probe templates for GADD153 were prepared from the plasmid pA5A4
(Fornace et al. 1989
) and for C/EBP-ß from MSV/EBP-ß
(Yeh et al. 1995
). Probes for the p53, GADD45, GAS1,
GAS2, GAS3, GAS5 and GAS6 genes were prepared by polymerase chain
reaction (PCR) amplification of cDNA prepared from
growth-arrested 3T3 cells (Fleming et al. 1998
). The
PCR primers used were described previously (Fleming et al. 1997
).
Northern analysis.
20 µg of total RNA was separated on a 1.2% agarose gel. The gel was
stained with ethidium bromide to confirm that equal amounts were loaded
before transfer to a nylon membrane (Boehringer, Lewes, East Sussex,
UK). Probe templates were labeled with [
-32P]-dCTP
using a Megaprime labeling kit (Amersham International, Buckingham, UK)
to give specific activities of 5 x 108–5 x
109 Bq/µg. Hybridizations were carried out according to
standard protocols (Sambrook et al. 1989
), and the blots
were washed in 0.5 x 150 mmol NaCl/L · (15 mmol sodium
citrate/L)-1 (SSC) + 1% SDS at 65°C. The distribution of
radioactivity was determined by using a wire proportional counter
(Packard Instant Imager, Canberra-Packard, Pangbourne Bucks,
UK) and by autoradiography. The relative expression of each mRNA was
determined by measuring the amount of radioactivity in each band on the
Northern blot and correcting it for variations in loading and transfer
efficiency by reprobing the blots for 18S ribosomal RNAs. Where
multiple transcripts were present, the radioactivity associated with
both bands was assessed.
Statistical analysis.
The RNA used for the blots shown in Figure 1
, was derived from two separate placentas at each time
point. The RNA in Figures 2
and 3 was extracted
from the organs of four separate pups chosen at random. The duplicate
sample was taken from a different set of four
pups.Data shown in Figure 4
were analyzed by one-way ANOVA (Excel 5.0, Microsoft, Seattle, WA).
Means for tissues were compared with the least significant difference
test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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) indicates
that the multiple mRNAs are regulated coordinately.
Figure 1
shows the changes in GAS and GADD expression during the
development of the placenta from d 12, when the placenta is undergoing
the final stages of growth, through to d 22. It should, however, be
noted that the sample for d 12 was a complete conceptus, including the
fetus. Although the bulk of the mRNA was derived from the placenta,
which dominates at that stage, high levels of expression in the fetus
cannot be ruled out. The p53, GADD45 and GAS6 genes showed their
highest expression on d 12 of gestation. Thereafter, the mRNA levels
fell, although all the genes continued to be expressed at a lower
level. After placental growth slowed and ceased at ~d 19, the
expression of the GADD153 and C/EBP-ß genes increased. The levels of
GAS1 and GAS3 mRNA in the placenta were below the detection limit.
The pattern of gene expression in the heart from d 18 until to 2 d
after birth is shown in Figure 2
. By d 17 of gestation, the
heart is almost completely formed, and there are no further changes in
gross morphology until birth. The p53, GAS1, GADD45 and GAS3 genes all
showed the highest levels of expression on gestational d 18. Expression
then declined as gestation progressed. The fall in p53 and GAS3 mRNA
levels was more pronounced than that of GAS1 and GADD45. The expression
of GADD153 increased slightly, reaching a maximum by d 2 after birth.
The expression of C/EBP-ß, which was low during gestation, showed a
marked increase after birth. The pattern of GAS6 expression in the
heart was very different from that found in the placenta and kidney. It
was expressed at a relatively constant level from gestational d
18 onwards, with only a slight drop on d 1 after birth.
The kidneys develop somewhat later than the other organs. Wilson & Warkany (1949
) showed that the metanephroi first appear on d
13, the first glomeruli are not present until d 18 and that the final
formation of the nephrons is not complete until after birth. Growth
arrest gene expression shown in Figure 3
, can be divided into three
periods. Early in the formation of the kidney, the p53, GAS1 and GAS3
genes were expressed. Between d 19 and 21 there was a second phase
characterized by a peak in the expression of GAS6, and finally, just
after birth, there was a considerable increase in the expression of
C/EBP-ß. The GADD45 gene was expressed throughout kidney development,
with a small increase during the late stages of gestation and just
after birth.
|
. For simplicity the genes have been divided into
three groups on the basis of their reported responses to
different stresses. (Linke et al. 1996
, Wang et al. 1996
) The first group are associated with the inhibition of
DNA synthesis and include the p53, GAS1 and GADD45 genes. The
expression of p53 was highest in the kidneys and lowest in the
placenta, with intermediate levels in the heart. The levels of GAS1 in
the kidneys were significantly higher than those in the heart and
placenta. The expression of GADD45 was lower in the heart than in
placenta and kidney, although the differences were not as marked as
those seen for p53 and GAS1.
The second group of genes, the GADD153 gene and the related bZip
transcriptional activator C/EBP-ß are associated with the inhibition
of protein synthesis. (Wang et al. 1996
)
Expression of the GADD153 was widespread, and there were no significant
differences among the three tissues. The expression of C/EBP-ß was
significantly higher in the placenta than in the heart or kidney.
The third group, the products of the GAS3 and GAS6 genes, are associated with the cell surface, the control of apoptosis and cell adhesion. Expression of GAS3 was highest in the kidney, intermediate in the heart and lowest in the placenta. The expression of GAS6 was significantly higher in the heart, with lower levels in the kidney and placenta.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). These results
show a change in the pattern of the nutrient-sensitive GAS and GADD
gene expression as development proceeds. As a generalization,
undifferentiated cells express higher levels of p53 and GAS1 and lower
levels of GADD153 and C/EBP-ß. There is a fall in p53 and GAS1 and an
increase in GADD153 and C/EBP-ß expression as the cells become
terminally differentiated. At any given stage in development there are
significant differences in GAS and GADD gene expression between
different organs because they are at different stages of development.
For example, the kidney, which is less advanced than the heart on d 19,
expresses significantly higher levels of p53 and GAS1. Low levels of
the mRNAs for these two genes are found in the placenta, which has
developed completely at this stage. The p53 protein mediates reversible
growth arrest in nucleotide deprived cells (Linke et al. 1996
), so if the mRNA levels reflect an increase in activity,
the sensitivity will decrease in the order kidney, heart and placenta.
Conversely, because the placenta has the highest levels of C/EBP-ß,
which is induced by amino acid deficiency (Fleming et al. 1998
), it will be more sensitive to growth arrest mediated
through this route.
There is toxicological evidence to support this hypothesis. The
inhibitor of nucleotide synthesis, phosphonacetyl
L-aspartic acid, induces apoptosis through a p53-dependent
mechanism and is embryotoxic when administered to pregnant mice. The
fetus is 20 times more sensitive during the first half of pregnancy
(Sieber et al. 1980a and 1980b
), showing that the early
stages of development are more sensitive to an interruption of the
nucleotide supply. This suggests that the increased levels of p53 mRNA
are associated with the presence of more functional protein. Accurate
DNA replication is of paramount importance because defects or errors
introduced at an early stage and left uncorrected would be propagated
through whole populations of cells. It was suggested that high levels
of the p53 gene in early embryonic cells serve to protect the
nutrient-stressed fetus by excluding these damaged cells
(Aladjem et al. 1998
).
In fibroblasts, the p53 protein interacts directly with the GAS1 gene
product, a plasma membrane glycoprotein that blocks the
G0 to S phase transition (Del Sal et al. 1995
). The biological function and mechanism of action of GAS1
are not yet understood. It was suggested that GAS1 may interact with
integrins and modify the attachment of cells to the extracellular
matrix (Evdokiou and Cowled 1998
). Because GAS1 is
expressed early during the development of both the heart and kidney, it
may be an important link between the nucleotide supply and organ
morphology. Although the GADD45 gene is also regulated by p53, other
factors, including C/EBP-, control its expression in terminally
differentiated cells (Constance et al. 1996
). The GADD45
gene product binds to the proliferating cell nuclear antigen, blocks
replication and allows DNA damage to be repaired before the cells enter
into the S phase (Smith et al. 1994
). Because GADD45
expression is largely independent of cell phenotype, it may be a useful
marker of a decrease in the available nucleotide supply or DNA damage
at any stage of gestation.
The increase in GADD153 and C/EBP-ß expression during the later
stages of fetal development may be a response to the increasing
metabolic demands as protein accretion approaches its maximum during
the latter stages of gestation. The C/EBP transcriptional activators
were shown to play an important part in the direct and indirect
regulation of growth. Directly, they regulate the normal
differentiation of cells, particularly those with extensive metabolic
functions, such as adipocytes and hepatocytes (Birkenmeier et al. 1989
, Yeh et al. 1995
). Indirectly, C/EBP
transcriptional activators may regulate the local production of growth
factors. The genes for insulin-like growth factor (IGF)-I and
IGF-II, growth hormone, leptin and various cytokines all
have C/EBP-binding sites in their promoters (Miller et al. 1996
, Nolten et al. 1994
, O'Brien et al. 1994
, Schaufele 1996
, van Dijk et al. 1992
). Fetal growth may be inhibited by a reduced production of
these and other growth factors and implies a shift towards a more
indirect regulation of growth during the latter stages of gestation.
The remaining growth arrest genes, GAS3 and GAS6, appear to be
regulated differently (Fleming et al. 1998
), and their
expression may be associated with specific cell interactions
(Antipatis et al. 1998
). The protein products have very
different functions: GAS3 is involved in the induction of apoptosis
(Fabbretti et al. 1995
), whereas the GAS6 gene product
regulates cell adhesion as well as being a protein tyrosine kinase
ligand (McCloskey et al. 1997
). By regulating adhesion
and apoptosis, these genes have an important role in the cell
interactions that shape tissue morphology. Both genes are expressed
during the development of the heart and kidney, and during these
periods specific, structures within the organs may be particularly
sensitive to nutrient deficiency.
The present results show that genes from the GAS and GADD families play a role in normal fetal development. Because these genes are not expressed uniformly in all fetal tissues, the response to nutrient deficiency may vary among different organs. Also, because their mRNA levels can be regulated in response to the nutrient supply, the specific timing of their expression may also define windows when particular organs are susceptible to the negative control of growth. This may produce asymmetrical fetal growth and development, which permanently changes the subsequent physiology of the adult.
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FOOTNOTES |
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2 N. F.-R. was the recipient of a scholarship
from the Boyd Orr Research Centre.
3 C. A. was the recipient of a scholarship
from the Greek State Foundation.
5 Abbreviations: GADD, growth arrest and DNA
damage; GAS, growth arrest specific; IGF, insulin-like growth
factor; PCR, polymerase chain reaction; SSC, 0.15 mol/L NaCl, 15 mmol/L
sodium citrate.
Manuscript received December 10, 1998. Initial review completed January 27, 1999. Revision accepted April 5, 1999.
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