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, -ß, and -
during Rat Embryonic Development1
Institut de Biologie Animale, Université de Lausanne, 1015 Lausanne, Switzerland
Address all correspondence and requests for reprints to: Dr. Walter Wahli, Institut de Biologie Animale, Bâtiment de Biologie, Université de Lausanne, CH-1015 Lausanne, Switzerland. E-mail: walter.wahli{at}iba.unil.ch
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Abstract |
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starts late in development,
with increasing levels in organs such as liver, kidney, intestine, and
pancreas, in which it will also be present later in adulthood to
regulate its specific target genes. PPAR is also transiently
expressed in the embryonic epidermis and central nervous system.
PPAR
presents a very restricted pattern of expression, being
strongly expressed in brown adipose tissue, in which differentiation it
has been shown to participate. Like PPAR, it is also expressed
transiently in the central nervous system. Interestingly, PPAR, -ß
and - are coexpressed at high levels in brown adipose tissue.
Finally, the high and ubiquitous expression of PPARß suggests some
fundamental role(s) that this receptor might play throughout
development. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, PPARß (also called 
, NUC-1, or
FAAR), and PPAR (2, 3, 4, 5, 6, 7, 8, 9, 10). PPARs were shown to be activated by
substances that induce peroxisome proliferation (2, 3) as well as by
natural fatty acids (4, 11). It is only recently that fatty acids, some
eicosanoids, and some hypolipidemic and antidiabetic drugs have been
shown to directly bind to PPARs (12–18; see Ref. 19 for a review).
PPAR target genes encode enzymes involved in peroxisomal and
mitochondrial ß-oxidation, ketone body synthesis, and microsomal
-hydroxylation, as well as the production of fatty acid binding
proteins, apolipoproteins, lipoprotein lipase, malic enzyme,
phosphoenolpyruvate carboxykinase, and the brown adipose tissue (BAT)
uncoupling protein (see Refs. 1, 20, and 21 for reviews; 22). Thus,
PPARs play key roles in different aspects of lipid metabolism and
homeostasis. Consistent with the different pathways they regulate,
PPARs were shown to be expressed in a wide range of tissues of the
adult organism (3, 7, 23, 24, 25). We have shown recently, using in
situ hybridization, that in the adult rat, PPAR is expressed in
cells with high catabolic rates of fatty acids and high
peroxisome-dependent activities (hepatocytes, cardiomyocytes, proximal
tubules of kidney, intestinal mucosa). PPARß is expressed
ubiquitously and is abundant in most tissues, whereas PPAR is
restricted mainly to adipose tissue, with some expression also in parts
of the immune system, the retina, and other organs in trace amounts
(25). The localization of PPAR and PPAR gene transcripts and
proteins and the nature of their target genes indicates that they play
roles in fatty acid catabolism for PPAR, on the one hand, and
adipogenesis and lipid storage for PPAR, on the other hand (see Ref.
1 for a review). In contrast, however, the role of the ubiquitously
expressed PPARß remains elusive.
As the ubiquitous expression of PPARß in the adult rat did not
provide clear information as to its roles, developmental expression of
this isotype was analyzed, with the goal of unraveling differential
patterns of expression that would implicate PPARß in specific events.
Developmental patterns of expression of PPAR and PPAR were also
investigated to further understand their roles in the embryo. Previous
reports of Northern blot analyses in Xenopus and mice showed
that PPARß is expressed early and throughout development, whereas
PPAR and PPAR appear only later in relatively high amounts (3, 7). However, these studies did provide only limited information, as the
distribution within the embryo could not be resolved by the approach
used. It is precisely to answer this question that analysis of the
differential tissular expression of PPARs during embryonic development
of the rat was undertaken by in situ hybridization. Rat
embryos were studied using specific probes for rat PPAR, PPARß,
and PPAR (25). Embryonic days (E) E8.5, E11.5, E13.5, E15.5, and
E18.5 were chosen to cover the most important periods of development:
E8.5 for the beginning of organization of the embryo in three layers;
E11.5–E15.5 because of the intense differentiation processes that
occur in most tissues, particularly in the central nervous system
(CNS); and E18.5 because it represents a stage at which many tissues
are already expressing specific functions that can be compared with
those found in adulthood. Our results show that PPAR and PPAR
start to be expressed only late in development (E13.5), mainly in the
tissues where they will be found postnatally and in the adult. In
addition, both PPAR and PPAR present transient expression in the
CNS around E13.5. In contrast to the specific distribution of PPAR
and PPAR, PPARß is expressed ubiquitously and very early during
embryogenesis, with a peak of expression in the developing nervous
system on E13.5. During late development (E18.5), PPARß decreases to
levels that will be found later ubiquitously in adult tissues. This
strikingly high expression of PPARß during development points to
potential new directions of investigation to analyze the to date
elusive role of this PPAR isotype.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(nucleotides 1377–1766) (4) was obtained (25, 26). cDNAs comprising
part of the A/B domain of the rat PPARß (nucleotides 264–398) (8)
and part of the A/B and C domains of the rat PPAR (403 nucleotides
long, 96% homologous to the mouse PPAR) (23) were obtained (25).
The three rat PPAR (, ß, and ) cDNAs were subcloned in
pBluescript KS+ and SK+ vectors (Stratagene,
Heidelberg, Germany) and used to synthesize in vitro
transcribed antisense and sense riboprobes (25, 27). Antisense and
sense riboprobes were labeled with digoxigenin (Boehringer Mannheim,
Mannheim, Germany).
Embryo preparation and in situ hybridization analysis
The age of Sprague-Dawley rat embryos (BRL, Basel, Switzerland)
was determined from the appearance of a vaginal plug in pregnant
females, and uteruses were dissected out. E8.5 embryos were let
in utero, whereas E11.5, E13.5, E15.5, and E18.5 embryos
were removed from the uterus and separated from the placenta. Uteruses
(E8.5) and embryos (E11.5, E13.5, E15.5, and E18.5) were then quickly
washed in diethylpyrocarbonate (Fluka, Buchs, Switzerland)-treated PBS
and fixed 15 h in 4% paraformaldehyde-PBS at room temperature.
Embryos were cryoprotected at 4 C in 12% sucrose-PBS and 18%
sucrose-PBS for 6 and 12 h, respectively, and then embedded in
tissue-freezing medium (Jung, Nussloch, Germany) and frozen in
isopentane and dry ice. Embryos were kept at -80 C until used, and
then cut and analyzed by in situ hybridization as previously
described (25, 27). Briefly, cryosections 12 µm thick were prepared,
and hybridization with digoxigenin-labeled antisense and sense
riboprobes for rat PPAR, -ß, and - was carried out at 60 C in
5 x SSC (standard saline citrate) and 50% formamide for 40
h. Washes (30 min in 2 x SSC at room temperature, 1 h in
2 x SSC at 65 C, 1 h in 0.1 x SSC at 65 C) and
alkaline phosphatase staining were performed as previously described
(25, 27). After staining, sections were dehydrated and mounted (Eukitt,
O. Kindler Co., Freiburg, Germany). The specificity of hybridization
was ascertained by the use of sense probes for the PPAR genes with the
same length, GC content, and specificity as the corresponding antisense
probes.
Histological analysis
In situ hybridization slides were observed and
photographed on an Axiophot microscope (Carl Zeiss, Zurich,
Switzerland).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PPAR
Transcripts of the PPAR gene were first detected at stage
E13.5, where they were found at relatively high levels in the CNS
(brain and spinal cord), tongue, and digestive tract (Fig. 1C
). Lower levels were also detected in
vertebrae, liver, and heart. On E15.5, PPAR expression decreased in
the CNS, heart, digestive tract, and vertebrae (Fig. 2A), whereas it remained unchanged in the
liver and was first detected in the epidermis, the cortex of the
kidney, striated muscles, and the lung (Fig. 2C and Table 1). On E18.5, the PPAR gene was highly
expressed in the liver (Fig. 3A and Table 1), the mucosa of the digestive tract (Fig. 3B and Table 1), BAT (Fig. 3C and Table 1), and epidermis (Fig. 3A and Table 1). PPAR
transcripts were also well detected in the kidney cortex and pancreas
(Fig. 3B and Table 1), but were barely detectable in muscle (Fig. 3, A
and C) and CNS (not shown and Table 1). The staining of sections with a
sense control probe for PPAR was negative at the different stages
tested (Figs. 1D and 3D).
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and Table 1), and the parietal
endoderm (Fig. 1E and Table 1). On E11.5, PPARß transcripts were
present in the CNS (brain and spinal cord), the first branchial arch,
and the bud of the digestive tract (Fig. 1F and Table 1). On E13.5,
E15.5, and E18.5, PPARß expression was ubiquitous, with relative
levels of transcripts varying from one tissue to another (Figs. 1G; 2,
D–F; and 3, E–I; and Table 1). An impressive peak of expression was
observed between E13.5–E15.5 (Figs. 1F and 2D and Table 1), followed
by a decrease on E18.5 (Fig. 3, E–I) to reach the levels of ubiquitous
expression found in the adult rat (25). The peak of PPARß transcripts
was particularly high on E13.5 in the CNS (whole brain and spinal
cord), the spinal ganglia, the tongue, the vertebrae, the liver, and
the digestive tract. It was also clearly observed in the heart and
epidermis, but at lower levels (Fig. 1G and Table 1). On E15.5, PPARß
was still very highly expressed in the CNS (whole brain and spinal
cord), particularly in the forebrain (telencephalic cortex; Fig. 2, D
and E, and Table 1). The liver, lung, digestive tract, and vertebrae
also presented high levels of PPARß messenger RNAs (mRNAs), whereas
it was found at lower levels in epidermis, heart, pancreas, and
squeletic muscle on E15.5 (Fig. 2, D and F, and Table 1). On E18.5,
very high amounts of PPARß transcripts were detected in the epidermis
and BAT (Fig. 3, G and I, and Table 1), as well as in the follicles of
vibrissae, primordia of teeth, and olfactory epithelium (Fig. 3I). It
was also well expressed in the mucosa of the digestive tract, the
cortex of the kidney, and the pancreas (Fig. 3F), as well as in
squeletic muscle, heart, and lung (Table 1 and not shown).
Interestingly at this stage, PPARß expression was decreased in the
liver (Fig. 3F and Table 1) and the CNS (Fig. 3E and Table 1). The
staining of sections with a sense control probe for PPARß was
negative in the different stages tested (Figs. 1H, 2I, and 3H).
PPAR
The expression of the PPAR gene was first detected on E13.5,
when relatively high transient levels of transcripts were observed in
the CNS only, particularly in the hindbrain (Fig. 1K). On E15.5, the
expression of PPAR in the CNS was already reduced, and no other
tissue was found expressing it (Fig. 2G and Table 1). On E18.5, PPAR
mRNAs were only detected in BAT, at very high levels (Fig. 3K and Table 1). The staining of sections with a sense control probe for PPAR was
negative at each stage tested (Figs. 1L, 2H, and 3L).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and PPAR appear late in
development in the tissues where they will continue to be expressed in
adulthood (25, 28), with the exception of a transient expression in the
CNS ( and ) and the epidermis (). In contrast, PPARß is
already expressed ubiquitously at the earliest stage tested, with a
marked peak on E13.5–E15.5, then declining to levels characteristic of
adulthood (25).
Late expression of PPAR in embryogenesis
The late onset of PPAR expression (E13.5) in liver, cortex of
kidney, intestinal mucosa, pancreas, and heart (this work and Ref.29)
correlates with the progressive differentiation of these organs (30),
including the maturation of specific metabolic pathways in which
PPAR has been found to be involved (see Ref. 1 for a review).
Particularly, the expression of PPAR in the developing liver,
kidney, and intestinal mucosa at the starting point of their
differentiation makes it possible to regulate, early in histogenesis,
the peroxisomal ß-oxidation-encoding genes that are expressed in the
primordials of these tissues before they differentiate (31). The
expression of PPAR in rat fetal pancreas (E18.5) may indicate its
involvement in insulin-secreting ß-cells just before they change
their metabolism from high fatty acid oxidation toward high glucose
oxidation on E19.5 (32). PPAR knock-out mice develop normally and
are fertile, without observable gross defects (33). Thus, either the
role(s) of PPAR in metabolic pathways must be very subtle during
embryogenesis, or compensatory events, e.g. by the other
PPAR isotypes, are responsible for the apparently normal development of
PPAR knock-out mice. PPARs could not be detected in the adult
epidermal keratinocytes by the technique used herein (25). In contrast,
we show in this study that PPAR and PPARß are expressed in the rat
embryonic epidermis. In the mouse embryo, PPAR and PPARß mRNAs
appear even earlier, together with PPAR, which we did not observe in
the rat (Michalik, L., and W. Wahli, personal communication). The
earlier onset of PPAR and PPARß in the mouse probably reflects the
2-day advance shift of mouse development compared with that in the rat
(30), whereas the difference in PPAR expression in embryonic
epidermis as well as liver is illustrative either of differences
between species or of the sensitivity of the methods used. However, it
indicates that PPARs might be involved in the establishment of the skin
lipid barrier, as suggested previously (34), based on a study using a
mouse expressing a dominant negative retinoic acid receptor.
Transient expression of PPAR and PPAR in the developing
CNS
Interestingly, a transient peak of expression of PPAR is
observed in the whole developing CNS, around the E13.5 stage. The same
phenomenon is true for PPAR, but is restricted to hindbrain. E13.5
corresponds to the onset of differentiation and apoptosis events in
CNS, which would suggest a role for PPAR and PPAR during these
processes, but remains to be proven.
Coexpression of PPAR, -ß, and - in BAT
White adipose tissue is specialized to store triglycerides
and releases fatty acids upon demand, whereas BAT has the additional
unique faculty to produce heat. This heat dissipation is made possible
by the expression of a specific BAT protein, UCP, which uncouples the
fatty acid oxidation from the synthesis of ATP (35, 36). Transgenic
mice lacking BAT develop obesity (37), providing evidence for an
important role of BAT in fatty acid catabolism. Furthermore, the
specific expression of UCP in BAT is regulated by PPAR (22), which
also promotes BAT differentiation at the end of fetal life (28). Our
results on PPAR expression in embryonic rat BAT underscore and add
to these data. Furthermore, we show that the two other isotypes,
PPAR and PPARß, are concomitantly expressed at high levels with
PPAR (this work and Ref.29). This raises the question of the
specific role(s) for each of the three receptors for BAT
differentiation and functions. Can they all achieve the PPAR
function in this developing tissue as previously reported (28), or do
PPAR and PPARß have different specific roles? One would predict
that as in adulthood, PPAR is involved primarily in BAT
differentiation and fatty acid uptake and storage, whereas PPAR
would regulate BAT fatty acid catabolism. Finally, PPARß would have a
role in basal cellular metabolism, in line with its ubiquitous
expression.
Potential roles of PPARß
PPARß is expressed ubiquitously, at higher levels during
embryogenesis than in adulthood (this study and Ref.25). It has been
proposed as a repressor of other PPAR isotype activities (38), but its
expression levels and pattern during development, compared with those
of the and isotypes, argue for a different function. Its
ubiquitous expression suggests a specific role in each cell type, from
the early embryo to adulthood, possibly under the control of specific
ligands. One possibility could be a function in membrane lipid
synthesis and turnover. Such a role is compatible with PPARß
expression in giant neurons of the adult brain (25), as these cells are
characterized by huge dendritic trees and axons that need high amounts
of membrane lipids and an efficient rate of membrane turnover both to
maintain these structures and to remodel synaptic connections. Another
possibility would be a function of PPARß at the onset of
differentiation processes. Indeed, we show that the peak of ubiquitous
expression of PPARß during embryogenesis correlates with that of the
period of greatest cell differentiation activity (30), particularly in
the CNS (39, 40). One hypothesis would view PPARß as a sensor for a
specific ligand that would induce cell differentiation, whereas the
absence of ligand would direct the cell toward apoptosis by default, as
previously suggested (36). This would be consistent with the PPARß
expression pattern in the adult, where it is found at high levels in
tissues with a high rate of cell renewal and differentiation (25).
Conclusion
We have described the expression patterns of the three PPAR
isotypes during embryonic development of the rat. PPAR and PPAR
appear late in development, in cells where they will be expressed later
in adulthood, e.g. liver, intestine, kidney, and pancreas
for , and adipose tissue for . Furthermore, an
interesting transient peak of expression of and has been
noticed in the CNS. The intriguing high coexpression of the three
isotypes in the developing BAT and CNS provides opportunities to define
their respective roles in these differentiating structures.
Furthermore, the very strong ubiquitous PPARß expression throughout
development argues for a role of this isotype in basic cellular
metabolic pathways, such as those involved in membrane synthesis and
turnover, and possibly in cell cycle control.
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Acknowledgments |
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Footnotes |
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2 Present address: Laboratoire de Chimie Clinique, Centre Hospitalier
Universitaire Vaudois, 1011-Lausanne, Suisse.
Received December 2, 1997.
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References |
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 R. K. Vikramadithyan, K. Hirata, H. Yagyu, Y. Hu, A. Augustus, S. Homma, and I. J. Goldberg Peroxisome Proliferator-Activated Receptor Agonists Modulate Heart Function in Transgenic Mice with Lipotoxic Cardiomyopathy J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 586 - 593. [Abstract] [Full Text] [PDF]
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Y. Wang, D. Botolin, B. Christian, J. Busik, J. Xu, and D. B. Jump Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases J. Lipid Res., April 1, 2005; 46(4): 706 - 715. [Abstract] [Full Text] [PDF]
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 N. Di-Poi, C. Y. Ng, N. S. Tan, Z. Yang, B. A. Hemmings, B. Desvergne, L. Michalik, and W. Wahli Epithelium-Mesenchyme Interactions Control the Activity of Peroxisome Proliferator-Activated Receptor {beta}/{delta} during Hair Follicle Development Mol. Cell. Biol., March 1, 2005; 25(5): 1696 - 1712. [Abstract] [Full Text] [PDF]
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S. A. Balaguer, R. A. Pershing, C. Rodriguez-Sallaberry, W. W. Thatcher, and L. Badinga Effects of Bovine Somatotropin on Uterine Genes Related to the Prostaglandin Cascade in Lactating Dairy Cows J Dairy Sci, February 1, 2005; 88(2): 543 - 552. [Abstract] [Full Text] [PDF]
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J. C. Corton and P. J. Lapinskas Peroxisome Proliferator-Activated Receptors: Mediators of Phthalate Ester-Induced Effects in the Male Reproductive Tract? Toxicol. Sci., January 1, 2005; 83(1): 4 - 17. [Abstract] [Full Text] [PDF]
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K. Wada, A. Nakajima, H. Takahashi, M. Yoneda, N. Fujisawa, E. Ohsawa, T. Kadowaki, N. Kubota, Y. Terauchi, N. Matsuhashi, et al. Protective effect of endogenous PPAR{gamma} against acute gastric mucosal lesions associated with ischemia-reperfusion Am J Physiol Gastrointest Liver Physiol, August 1, 2004; 287(2): G452 - G458. [Abstract] [Full Text] [PDF]
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 C. Blanquart, R. Mansouri, R. Paumelle, J.-C. Fruchart, B. Staels, and C. Glineur The Protein Kinase C Signaling Pathway Regulates a Molecular Switch between Transactivation and Transrepression Activity of the Peroxisome Proliferator-Activated Receptor {alpha} Mol. Endocrinol., August 1, 2004; 18(8): 1906 - 1918. [Abstract] [Full Text] [PDF]
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 C. M. Holland, S. A. Saidi, A. L. Evans, A. M. Sharkey, J. A. Latimer, R. A.F. Crawford, D. S. Charnock-Jones, C. G. Print, and S. K. Smith Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets Mol. Cancer Ther., August 1, 2004; 3(8): 993 - 1001. [Abstract] [Full Text] [PDF]
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H. J. Lim, I. Moon, and K. Han Transcriptional Cofactors Exhibit Differential Preference toward Peroxisome Proliferator-Activated Receptors {alpha} and {delta} in Uterine Cells Endocrinology, June 1, 2004; 145(6): 2886 - 2895. [Abstract] [Full Text] [PDF]
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 N. Miyamura, T. Ogawa, S. Boylan, L. S. Morse, J. T. Handa, and L. M. Hjelmeland Topographic and Age-Dependent Expression of Heme Oxygenase-1 and Catalase in the Human Retinal Pigment Epithelium Invest. Ophthalmol. Vis. Sci., May 1, 2004; 45(5): 1562 - 1565. [Abstract] [Full Text] [PDF]
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 R. Nardacci, I. Falciatori, S. Moreno, and S. Stefanini Immunohistochemical Localization of Peroxisomal Enzymes During Rat Embryonic Development J. Histochem. Cytochem., April 1, 2004; 52(4): 423 - 436. [Abstract] [Full Text] [PDF]
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 A. Mouihate, L. Boisse, and Q. J. Pittman A Novel Antipyretic Action of 15-Deoxy-{Delta}12,14-Prostaglandin J2 in the Rat Brain J. Neurosci., February 11, 2004; 24(6): 1312 - 1318. [Abstract] [Full Text] [PDF]
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 M. C. Sugden and M. J. Holness Potential Role of Peroxisome Proliferator-Activated Receptor-{alpha} in the Modulation of Glucose-Stimulated Insulin Secretion Diabetes, February 1, 2004; 53(90001): S71 - 81. [Abstract] [Full Text]
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 R. G. Oshima, J. Lesperance, V. Munoz, L. Hebbard, B. Ranscht, N. Sharan, W. J. Muller, C. A. Hauser, and R. D. Cardiff Angiogenic Acceleration of Neu Induced Mammary Tumor Progression and Metastasis Cancer Res., January 1, 2004; 64(1): 169 - 179. [Abstract] [Full Text] [PDF]
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K. E. Schmid and L. A. Woollett Differential effects of polyunsaturated fatty acids on sterol synthesis rates in adult and fetal tissues of the hamster: consequence of altered sterol balance Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G796 - G803. [Abstract] [Full Text] [PDF]
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 A. Kono, C. Umeda-Hara, J. Lee, M. Ito, H. Uchimiya, and M. Umeda Arabidopsis D-Type Cyclin CYCD4;1 Is a Novel Cyclin Partner of B2-Type Cyclin-Dependent Kinase Plant Physiology, July 1, 2003; 132(3): 1315 - 1321. [Abstract] [Full Text] [PDF]
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M. Jalouli, L. Carlsson, C. Ameen, D. Linden, A. Ljungberg, L. Michalik, S. Eden, W. Wahli, and J. Oscarsson Sex Difference in Hepatic Peroxisome Proliferator-Activated Receptor {alpha} Expression: Influence of Pituitary and Gonadal Hormones Endocrinology, January 1, 2003; 144(1): 101 - 109. [Abstract] [Full Text] [PDF]
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 K Yamakawa-Kobayashi, H Ishiguro, T Arinami, R Miyazaki, and H Hamaguchi A Val227Ala polymorphism in the peroxisome proliferator activated receptor {alpha} (PPAR{alpha}) gene is associated with variations in serum lipid levels J. Med. Genet., March 1, 2002; 39(3): 189 - 191. [Full Text]
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T. Hatae, M. Wada, C. Yokoyama, M. Shimonishi, and T. Tanabe Prostacyclin-dependent Apoptosis Mediated by PPARdelta J. Biol. Chem., November 30, 2001; 276(49): 46260 - 46267. [Abstract] [Full Text] [PDF]
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P. Escher, O. Braissant, S. Basu-Modak, L. Michalik, W. Wahli, and B. Desvergne Rat PPARs: Quantitative Analysis in Adult Rat Tissues and Regulation in Fasting and Refeeding Endocrinology, October 1, 2001; 142(10): 4195 - 4202. [Abstract] [Full Text] [PDF]
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L. Michalik, B. Desvergne, N. S. Tan, S. Basu-Modak, P. Escher, J. Rieusset, J. M. Peters, G. Kaya, F. J. Gonzalez, J. Zakany, et al. Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR){alpha} and PPAR{beta} mutant mice J. Cell Biol., August 20, 2001; 154(4): 799 - 814. [Abstract] [Full Text] [PDF]
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N. Miyamura, K. Mishima, S. Honda, A. E. Aotaki-Keen, L. S. Morse, J. T. Handa, and L. M. Hjelmeland Age and Topographic Variation of Insulin-like Growth Factor-Binding Protein 2 in the Human RPE Invest. Ophthalmol. Vis. Sci., June 1, 2001; 42(7): 1626 - 1630. [Abstract] [Full Text]
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 U. Werling, S. Siehler, M. Litfin, H. Nau, and M. Göttlicher Induction of Differentiation in F9 Cells and Activation of Peroxisome Proliferator-Activated Receptor delta by Valproic Acid and Its Teratogenic Derivatives Mol. Pharmacol., April 16, 2001; 59(5): 1269 - 1276. [Abstract] [Full Text]
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 C. Wolfrum, C. M. Borrmann, T. Börchers, and F. Spener Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma -mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus PNAS, February 15, 2001; (2001) 51619898. [Abstract] [Full Text]
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T. Ohshima, M. Ogawa, Veeranna, M. Hirasawa, G. Longenecker, K. Ishiguro, H. C. Pant, R. O. Brady, A. B. Kulkarni, and K. Mikoshiba Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain PNAS, February 8, 2001; (2001) 51628498. [Abstract] [Full Text]
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M. Grabenbauer, H. D. Fahimi, and E. Baumgart Detection of Peroxisomal Proteins and Their mRNAs in Serial Sections of Fetal and Newborn Mouse Organs J. Histochem. Cytochem., February 1, 2001; 49(2): 155 - 164. [Abstract] [Full Text]
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 S. W. Han, M. E. Greene, J. Pitts, R. K. Wada, and N. Sidell Novel Expression and Function of Peroxisome Proliferator-activated Receptor Gamma (PPAR{{gamma}}) in Human Neuroblastoma Cells Clin. Cancer Res., January 1, 2001; 7(1): 98 - 104. [Abstract] [Full Text]
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J. M. Peters, S. S. T. Lee, W. Li, J. M. Ward, O. Gavrilova, C. Everett, M. L. Reitman, L. D. Hudson, and F. J. Gonzalez Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor beta (delta ) Mol. Cell. Biol., July 15, 2000; 20(14): 5119 - 5128. [Abstract] [Full Text]
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C. Huin, L. Corriveau, A. Bianchi, J. M. Keller, P. Collet, P. Krémarik-Bouillaud, L. Domenjoud, P. Bécuwe, H. Schohn, D. Ménard, et al. Differential Expression of Peroxisome Proliferator-activated Receptors (PPARs) in the Developing Human Fetal Digestive Tract J. Histochem. Cytochem., May 1, 2000; 48(5): 603 - 612. [Abstract] [Full Text]
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K. Bordji, J.-P. Grillasca, J.-N. Gouze, J. Magdalou, H. Schohn, J.-M. Keller, A. Bianchi, M. Dauca, P. Netter, and B. Terlain Evidence for the Presence of Peroxisome Proliferator-activated Receptor (PPAR) alpha and gamma and Retinoid Z Receptor in Cartilage. PPARgamma ACTIVATION MODULATES THE EFFECTS OF INTERLEUKIN-1beta ON RAT CHONDROCYTES J. Biol. Chem., April 14, 2000; 275(16): 12243 - 12250. [Abstract] [Full Text] [PDF]
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 C. Shachaf, K. L. Skorecki, and M. Tzukerman Role of AP2 consensus sites in regulation of rat Npt2 (sodium-phosphate cotransporter) promoter Am J Physiol Renal Physiol, March 1, 2000; 278(3): F406 - F416. [Abstract] [Full Text] [PDF]
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S. Basu-Modak, O. Braissant, P. Escher, B. Desvergne, P. Honegger, and W. Wahli Peroxisome Proliferator-activated Receptor beta Regulates Acyl-CoA Synthetase 2 in Reaggregated Rat Brain Cell Cultures J. Biol. Chem., December 10, 1999; 274(50): 35881 - 35888. [Abstract] [Full Text] [PDF]
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 B. Desvergne and W. Wahli Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism Endocr. Rev., October 1, 1999; 20(5): 649 - 688. [Abstract] [Full Text]
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 H. Lim, R. A. Gupta, W.-g. Ma, B. C. Paria, D. E. Moller, J. D. Morrow, R. N. DuBois, J. M. Trzaskos, and S. K. Dey Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta Genes & Dev., June 15, 1999; 13(12): 1561 - 1574. [Abstract] [Full Text]
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T. Kojima, Y. Morikawa, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, E. Senba, and T. Kitamura TROY, a Newly Identified Member of the Tumor Necrosis Factor Receptor Superfamily, Exhibits a Homology with Edar and Is Expressed in Embryonic Skin and Hair Follicles J. Biol. Chem., June 30, 2000; 275(27): 20742 - 20747. [Abstract] [Full Text] [PDF]
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M. Elholm, I. Dam, C. Jorgensen, A.-M. Krogsdam, D. Holst, I. Kratchmarova, M. Gottlicher, J.-A. Gustafsson, R. Berge, T. Flatmark, et al. Acyl-CoA Esters Antagonize the Effects of Ligands on Peroxisome Proliferator-activated Receptor alpha Conformation, DNA Binding, and Interaction with Co-factors J. Biol. Chem., June 8, 2001; 276(24): 21410 - 21416. [Abstract] [Full Text] [PDF]
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D. C. Jones, X. Ding, and R. A. Daynes Nuclear Receptor Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Is Expressed in Resting Murine Lymphocytes. THE PPARalpha IN T AND B LYMPHOCYTES IS BOTH TRANSACTIVATION AND TRANSREPRESSION COMPETENT J. Biol. Chem., February 22, 2002; 277(9): 6838 - 6845. [Abstract] [Full Text] [PDF]
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C. Wolfrum, C. M. Borrmann, T. Borchers, and F. Spener Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma -mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus PNAS, February 27, 2001; 98(5): 2323 - 2328. [Abstract] [Full Text] [PDF]
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T. Ohshima, M. Ogawa, Veeranna, M. Hirasawa, G. Longenecker, K. Ishiguro, H. C. Pant, R. O. Brady, A. B. Kulkarni, and K. Mikoshiba Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain PNAS, February 27, 2001; 98(5): 2764 - 2769. [Abstract] [Full Text] [PDF]
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