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Dynamic Transcriptional Changes of TIEG1 and TIEG2 During Mouse Tissue Development.

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THE ANATOMICAL RECORD 293:858?864 (2010)
Dynamic Transcriptional Changes of
TIEG1 and TIEG2 During Mouse Tissue
Institute of Cell Biology, Zhejiang University, Hangzhou, People?s Republic of China
Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of
Hong Kong, Shatin, HKSAR
Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
Shatin, HKSAR
Department of Surgery, The Chinese University of Hong Kong, Shatin, HKSAR
TGF-b-inducible early-response gene (TIEG) is a family of primary
response genes induced by TGF-b, which are well recognized in regulating cellular proliferation and apoptosis. However, their expression pro?le
has never been investigated during embryogenesis in different organs. In
this study, we aimed to investigate the transcriptional level of both
TIEG1 and TIEG2 during development in various mice organs, including
the brain cortex, cerebellum and stem, brain striatum, muscle, heart,
liver, kidney, and lung. Quantitative real-time PCR was used to pro?le
the change of transcriptional level of the two TIEG members in the mice
tissues at six developmental stages. Taken together, the expression of
TIEG1 and TIEG2 was speci?c in different organs yet varied with different developmental time points. Their dynamic changes were moderately
consistent in most organs including the brain cortex, striatum, liver, kidney, and lung. However, their mRNA expression in both the heart and
muscle was signi?cantly different at all developmental stages, which
might propose a compensation of functions in the TIEG family. Nevertheless, our data indicate that both the TIEG genes are essential in regulating the normal organ development and functioning in murine model, as
their expressions were ubiquitous and tissue speci?c at various developC 2010 Wiley-Liss, Inc.
mental stages. Anat Rec, 293:858?864, 2010. V
Key words: TIEG1; TIEG2; embryogenesis; mRNA expression
Transforming growth factor-beta (TGF-b) and other
growth factors constitute a large family of multifunctional proteins, which are known to regulate various bio-
logical processes including cell growth, proliferation,
differentiation, and apoptosis (Padgett et al., 1998; Chen
and Meng, 2004). They are capable to induce various
Lei Jianga and Yangchao Chen contributed equally to this work.
Grant sponsors: Hong Kong Research Grants Council (GRF
Grant); Grant numbers: CUHK462109, CUHK7422/03M, 467507;
Grant sponsor: Special Grant of the Major State Basic Research
Program of China; Grant number: 2006CB910100; Grant sponsor:
Foundation of Guangzhou Science and Technology Bureau; Grant
number: 2005Z1-E013; Grant sponsors: Chinese University of
Hong Kong, Li Ka Shing Institute of Health Sciences.
*Correspondence to: Ji-Cheng Li, Institute of Cell Biology,
Zhejiang University, Hangzhou, 310058, Zhejiang Province,
People?s Republic of China. E-mail: Phone:
�-571-88208088; Fax: �-571-88208094. or H.-F. Kung,
Stanley Ho Centre for Emerging Infectious Diseases, Rm511A,
Basic Medical Sciences Building, The Chinese University of
Hong Kong, Shatin, HKSAR. E-mail:
Phone: �2-2603-7743; Fax: �2-2994-4988.
Received 5 November 2008; Accepted 1 December 2009
DOI 10.1002/ar.21108
Published online 3 March 2010 in Wiley InterScience (www.
cellular responses via particular receptor complex and
Smad proteins, which depend on cell type and stimulation context (Rahimi and Leof, 2007). For example, they
can induce growth arrest (i.e., apoptosis) in epithelial
cells, which is a crucial step in suppressing tumors
(Padgett et al., 1998; Sanchez et al., 1999; Cao et al.,
2006). However, the TGF-b signaling pathway is also
capable to promote carcinogenesis via induction of epithelial-mesenchymal transition (Rane et al., 2006; Caja
et al., 2007).
TGF-b-inducible early-response gene (TIEG) is a family of primary response genes induced by TGF-b and was
originally identi?ed in human osteoblasts (Subramaniam
et al., 1995). They are inducible by estrogen, an important anabolic hormone in the bone (Tau et al., 1998).
TIEG gene encodes 480 amino acids and is regarded as
one member of the Kru?ppel-like family of transcription
factors (Fautsch et al., 1998; Chrisman and Tindall,
2003). TIEGs are involved in TFG-b signal transduction
(Cook and Urrutia, 2000) and are playing signi?cant
roles in regulating cell proliferation and apoptosis in
various cell types (Tachibana et al., 1997; Ribeiro et al.,
1999). Upon overexpression, TIEG1 enhanced TGF-b
induction of Smad-binding element reporter activity
(Johnsen et al., 2002a). Moreover, TIEG is thought to
act as an inducer of gene transcription via upregulating
the CD11d gene expression in myeloid cells (Noti et al.,
2004). So far, three isoforms of TIEGs (TIEG1, TIEG2,
and TIEG3) have been identi?ed. All of them contain
three C2H2 zinc ?ngers near the C-terminus and one
praline-rich N-terminal regulatory domain (Cook et al.,
1999; Wang et al., 2004). All their mRNA expression can
be upregulated in response to TGF-b1 treatment with
similar induction time course (Cook et al., 1999; Hefferan et al., 2000b). Moreover, they have all been identi?ed in mouse (Yajima et al., 1997; Fautsch et al., 1998;
Wang et al., 2004), whereas only two of them, TIEG1
and TIEG2, are identi?ed in human (Subramaniam
et al., 1995; Cook et al., 1998). In general, TIEG2 shares
91% homology with TIEG1 within the zinc ?nger region
(Cook et al., 1999), whereas TIEG3 shows 26 and 66%
similarity to TIEG1 and TIEG2, respectively (Wang
et al., 2004).
Recently, signi?cant defect has been demonstrated in
both osteoblasts and osteoclasts using a TIEG1 knockout mice model, which suggests a crucial role of TIEG1
in osteoblast function and osteoclast differentiation
(Subramaniam et al., 2005). Using the same model in a
later study, TIEG1 was shown to contribute signi?cantly at an age-dependent manner in the growth and
maintenance of tendon microarchitecture and strength
(Bensamoun et al., 2006b). In another study, TIEG null
mice demonstrated severe and cardiac hypertrophy,
which suggested a pivotal role of TIEG in normal cardiac development and functioning (Rajamannan et al.,
2007). Moreover, TIEG1 overexpression was found to
mimic TGF-b action in human osteoblast cells by
increasing the alkaline phosphatase and decreasing
osteocalcin secretion (Hefferan et al., 2000a). Similar
mimicking effect was also observed in hepatocarcinoma
(Ribeiro et al., 1999), pancreatic carcinoma (Tachibana
et al., 1997), and mink lung epithelial cells (Chalaux
et al., 1999), for TIEG1 overexpression would induce
apoptosis and inhibit cell growth similar to that of
TGF-b. The transcriptional level of TIEG1 was found
signi?cantly reduced in breast cancer, rendering it one
of the most reliable markers to use with a sensitivity
and speci?city of 96 and 93%, respectively (Reinholz
et al., 2004).
TIEG2 is a pancreas-enriched transcription factor,
which can regulate exocrine cell growth and behaves as
a tumor suppressor (Fernandez-Zapico et al., 2003).
Recent studies have suggested TIEG2 as a potential endocrine regulator, while it might also play a pivotal role
in postprandial glucose metabolism of skeletal muscle
(Yamamoto et al., 2004). Besides, it can repress caveolin1 gene in adipose tissue in a cholesterol-dependent manner (Cao et al., 2005). Similar to TIEG1, the function of
TIEG2 has also been investigated using knockout mice
technique. However, no abnormalities were found in the
knockout model; thus, it was believed that TIEG2 might
not be a critical component in mice development (Song
et al., 2005). In an earlier study, TIEG2 was shown to
mimic the antiproliferative effects of TGF-b (Cook et al.,
1998). Because of the strong sequence homology between
TIEG1 and TIEG2, TIEG2 is also thought to involve in
the regulation of apoptosis (Cook et al., 1998). Transient
overexpression of TIEG2 has been reported to reduce the
activity of Bcl-XL promoter and to decrease the BCL-XL
protein level (Wang et al., 2007). It also induces Caspase3-dependent apoptosis in murine OLI-neu cells,
which suggests its role as a downstream mediator of
TGF-b that bridges the TGF-b signaling pathway with
the apoptotic intracellular pathway (Wang et al., 2007).
Although TIEGs are well recognized to regulate cellular proliferation and apoptosis, their expression pro?le
has not been investigated during embryogenesis in various organs. In this study, we aim to investigate the transcriptional level of both TIEG1 and TIEG2 during
development in various mice organs. Their exact roles in
developmental process in different organs are discussed.
Murine Embryos and Adult Tissues
Embryos were carefully isolated from ICR mice, which
were 12 (E12) and 16 (E16) days pregnant. Mice at various ages (i.e., 1 day, 8 days, 15 days, and adult mice)
were sacri?ced by cervical dislocation. Individual tissues
including brain cortex, cerebellum and stem (cere/stem),
striatum, muscle, heart, liver, kidney, and lung were dissected. Tissues were collected and immediately
immersed in liquid nitrogen. They were stored at 80 C
until use. All experimental procedures were approved in
prior by the Animal Experiment Ethics Committee of
the Chinese University of Hong Kong.
RNA Extraction and Reverse Transcription
Total RNA was isolated using TRIZOL reagent (Invitrogen). Each RNA sample (2 lg) was reverse-transcribed using the ImProm-IITM Reverse transcription
system (Promega) according to the manufacturer?s
Quantitative Real-Time PCR
The quantitation of mRNA was carried out using a
real-time ?uorescence detection method. Quantitative
real-time PCR (qRT-PCR) was performed using SYBRs
Fig. 1. Relative amounts of TIEG1 mRNA expression in different
organs during murine development. Gene expression value of E12 (BC
� BS � CS) was set as 100%, and the values of the other samples
were made relative to this value. E12, 12 day embryo; E16, 16 day
embryo; P1, postnatal day 1; P8, postnatal day 8; P15, postnatal day
15; A, adult; BC, brain cortex; CS, cerebellum and stem; BS, brain
striatum; L, liver; K, kidney; LU, lung; H, heart; M, muscle.
GREEN PCR Master Mix (Applied Biosystems, Warrington, UK) and an ABI 7500 real-time PCR system
(Applied Biosystems). DNA content was determined by
measuring the real-time ?uorimetric intensity of SYBR
green I incorporation after completion of the primer
extension step in each cycle. A melting curve program
was used to monitor the PCR product and to distinguish
the samples from primer dimmers or other nonspeci?c
products. Mock real-time PCR was also performed to
evaluate genomic DNA contamination. A control housekeeping gene mouse glyceraldehyde-3-phosphate dehydrogenase (GADPH) was used as an internal control for
normalizing variations due to differences in RNA quantity or ef?ciency of reverse transcription. The primers
used in this study are listed as follows: TIEG1 forward
primer: 50 -GCT CAA CTT CGG CGC TTC TC-30 , reverse
primer: 50 -ACT TCC AGT CGC AGC TCA TG-30 ; TIEG2
forward primer: 50 -TCC CGA AGG AGG AAC TAT GT-30 ,
reverse primer: 50 -CCT GGG ATC TTC TTG GTT GT-30 ;
GAPDH forward primer: 50 -AAC ATC AAA TGG GGT
GAG GCC-30 , reverse primer: 50 -GTT GTC ATG GAT
GAC CTT GGC-30 . The relative amount of mRNA
expression of various samples was normalized to the
level of GADPH. Standard expression curves for genes
were also performed using a threefold dilution series of
cDNAs derived from brain cortex of embryo of 12 days of
age using RT-PCR. The expression level of both TIEG1
and TIEG2 in various tissues was divided by the corresponding expression level of GAPDH, thus to obtain the
?nal normalized value. In every group, the mRNA
expression level of TIEG in the brain cortex of the Day
12 embryo (E12BC) was set as 100%, and each of their
values found in other organs were compared and made
relative to the E12BC value. Three independent experiments were carried out for each sample, and duplicate
results were used to calculate the geometric mean.
Tissue-Speci?c TIEG1 and TIEG2 Expression
During Murine Development
As the brain cortex, brain striatum, and cere/stem
were not well distinguished from each other at E12
stage, the whole brain tissues (marks as BC � BS � CS
in the ?gures) were used for examining the TIEG level.
In Figs. 1 and 2, they show the relative changes of
TIEG1 and TIEG2 mRNA expression at different developmental stages in various organs, respectively. Based
on our observation, TIEG1 and TIEG2 were expressed
speci?cally in different organs yet varied with different
developmental time points. Moreover, the expression
level of TIEG1 in most of the organs at all of the developmental stages was signi?cantly higher than those of
TIEG2. These might indicate that the TIEG1 is playing
a relatively more crucial and essential role in regulating
the development of murine organs than that of TIEG2.
In Figs. 3 and 4, the data shown for the brain cortex,
cere/stem, and brain striatum were their estimated values derived from the corresponding total TIEG1 or
TIEG2 expression level in the brain, respectively. In
Fig. 2. Relative amounts of TIEG2 mRNA expression in different organs during murine development.
Fig. 3. Dynamic change of TIEG1 mRNA expression in various organs during murine development.
Fig. 4. Dynamic change of TIEG2 mRNA expression in various organs during murine development.
general, mRNA expression of TIEG1 and TIEG2 was low
in the brain at all developmental stages. As seen in
Fig. 3A, the brain cortex revealed a relatively higher
expression of TIEG1 at P1 and P8. Similar pattern of
expression was not followed by the cere/stem (Fig. 3B),
yet could be observed in other brain compartment, such
as the striatum with different extent (Fig. 3C). On the
other hand, the TIEG2 gene appeared to be transiently
induced in the brain cortex, cere/stem, and brain striatum at both the P1 and P8 stages (Fig. 4A?C). In the
liver, the relative expression of TIEG1 and TIEG2 varied
in similar pattern with their peak expressions noted at
P1 (Fig. 3D) and P8 (Fig. 4D), respectively. Besides, the
relative mRNA expression of TIEG1 kept increasing
from E12 to P8 in the kidney, but signi?cantly lower
expression was observed at P15 and adult (Fig. 3E).
Similar pattern of increment was also observed for
TIEG2 in the kidney (Fig. 4E). For TIEG1, a signi?cantly higher mRNA expression was observed in the
lung with the peak expression recorded at P1 and then
P8 (Fig. 3F), whereas highest level of TIEG2 was
observed at P8 and then P1 (Fig. 3G). The expression
level of TIEG2 is generally lower than that of TIEG1 at
these two time points. In the heart, TIEG1 expressed
exclusively higher in the mature/adult heart, whereas it
remained at a very low level throughout development
(Fig. 4F). For TIEG2, its mRNA level was very low in
the heart at all stages including the mature heart (Fig.
4G). Finally, there was a markedly increase of TIEG1 in
the muscle from E12 to adult, yet most signi?cant
increase was noted between P8 and P15 (Fig. 3H).
Reverse pattern was noted for TIEG2 in the muscle tissues with the highest of its expression noted at E12 and
gradually decreased toward adolescence (Fig. 4H). Taken
together, the dynamic changes of TIEG1 and TIEG2
expressions were relatively consistent in most organs
including the brain cortex, striatum, liver, kidney, and
lung, but not in the heart and muscle cells.
In this study, the mRNA expression of both TIEG1 and
TIEG2 was pro?led during murine development. Their
expression level in various organs was investigated using
qRT-PCR at six developmental stages. According to our
data, the mRNA expression of both TIEG1 and TIEG2 is
tissue-speci?c manner at various developmental stages.
Their expression patterns were quite similar in most
organs including brain cortex, striatum, kidney, lung, and
liver, but not in the heart and muscle. These might indicate
a compensation of function in the TIEG family, particularly
during the ?nal developmental stage of the cardiac and
muscle cells. The ?ndings of this study provide the basic
understanding on the expression pro?le of TIEG family
during normal embryogenic and developmental stages.
This is crucial if one needs to further investigate how and
when to control these groups of proteins, which are closely
related to TFG-b family, in combating different carcinogenic conditions, such as hepatocarcinoma and lung cancer.
As seen in Fig. 1, low mRNA level of TIEG1 was found
in different brain compartments and liver, whereas high
level was expressed in the kidney during embryogenesis.
It agrees with previous study in which TIEG1 was also
observed in the brain, differentiating mesenchyme and
kidney (Yajima et al., 1997). In fact, TIEG1 has been
related to hippocampal network functioning via TGF-b
signaling pathway (Lacmann et al., 2007). It was upregulated in somata of postsynaptic granule cells following
both brain-derived neurotrophic factor- long-term potentiation and high-frequency stimulation-induced longterm potentiation (Wibrand et al., 2006). However, information of its role in brain development is still scarce. On
the other hand, TIEG1 is known to be regulated by connective TGF in human mesangial cells, thus enhanced
the TGF-b signaling pathway (Wahab et al., 2005). In
hepatal tissues, TIEG1 has been reported to induce apoptosis in hepatoma Hep3B cells (Ribeiro et al., 1999). In
addition, it was known to repress glutathione transferase P gene expression in rat liver and was found to be
useful in suppressing early stage of chemical hepatocarcinogenesis (Tanabe et al., 2002). However, the exact
role of TIEG1 in normal renal and hepatal development
is yet to be elucidated.
As mentioned earlier, TIEG1 is known to mimic TGF-b
action in mink lung epithelial cells (Chalaux et al., 1999).
Overexpression of TIEG1 may decrease endogenous Bcl-2
levels and elicit programed cell death. In this study, the
high expression of TIEG1 at the P1 and P8 stages may
indicate a stimulated apoptotic cell death in this organ at
this period of development. It could be a physiological
variation that used to mediate various cell growth and
proliferation at particular interval of murine development. Such upregulation could also be a response to the
stimulation of other factors, such as bone-morphogenetic
protein-2 (Hefferan et al., 2000b) or estrogen (Tau et al.,
1998). The high expression level of TIEG in the lung may
indicate high apoptotic rate, which could explain the high
regenerative activity in the lungs of younger mice.
In previous studies, TIEG1 was reported to express in
normal human myocardium (Subramaniam et al., 1995,
1998). The signaling pathway of TIEG1 was thought to
implicate cardiomyocyte growth and ?brosis (Li et al.,
1998), while absence of the gene resulted in cardiac hypertrophy (Rajamannan et al., 2007). Therefore, normal
expression level of TIEG is undoubtedly pivotal for normal heart development, which might explain the high
expression level of TIEG in the mature mice heart.
High TIEG expression has been reported in skeletal tissues and human osteoblasts (Subramaniam et al., 1995).
TIEG is believed to be a key regulatory factor in the TGFb action in the tissues. In addition, it was suggested to associate with Src homology-3 in the signal transduction
processes (Subramaniam et al., 1995). In an earlier
TIEG1 null mice model, the animals were physically
weaker than those of the wild types (Bensamoun et al.,
2006a). Previous study has also revealed a drastic drop of
bone content, density, and size in the animal model. Electron microscopy also demonstrated a signi?cant decrease
in osteocyte number in the TIEG1 knock out mice model,
which suggests a crucial role of TIEG1 in osteoblast differentiation. It is generally believed that TIEG1 is crucial for
healthy bone development (Bensamoun et al., 2006a).
Therefore, the exact functions of TIEGs in the muscle tissues warrant further investigations.
In this study, the expression of both TIEG isoforms
was generally low and steady throughout the developmental stages. In the oligodendroglial cell line, OLI-neu,
overexpression of TIEG has been found to downregulate
the protein expression of Bcl-2 family and to reduce the
antiapoptotic mediator, Bcl-XL, at both transcription and
translational levels (Bender et al., 2004). The induced
repression is nicely parallel with the TGF-b-induced apoptosis, which strongly indicates that the TIEG is a
downstream protein in the TGF-b-induced cell death. On
the other hand, Bcl-2 family members are known to play
a critical role in embryonic development. Recently,
TIEG2 has been reported to downregulate one of the
Bcl-2 family members, Bcl-XL, thus led to caspase-3-dependent apoptosis (Wang et al., 2007). Therefore, TIEG2
might act directly in regulating cell proliferation and apoptosis via enhancing the TGF-b signaling pathway, yet
they might also function through mediating the Bcl-2
family proteins. In the liver, TIEG2 was involved in complete gene regulation by functioning as an activator, that
increased monoamine oxidases B gene expression at promoter, mRNA, protein, and catalytic activity levels in
both the SH-SY5Y and HepG2 cells (Ou et al., 2004).
TIEG2 is also known to express ubiquitously in human
tissues, with enrichment in pancreas and muscle (Cook
et al., 1998). However, its functional role during embryogenesis and normal development has not been reported
in organs. With a 91% homology with TIEG1 within the
zinc ?nger region and 44% homology within the N terminus, it might be reasonable to postulate that TIEG2
shares similar function as TIEG1, but differs in their
scope of actions. Nevertheless, TIEG is believed to act as
repressor of Smad7 (Johnsen et al., 2002b) and an
enhancer for SBE promoter activity (Bender et al.,
2004), which exempli?es the complex functions of the
TIEG proteins.
In this study, qRT-PCR is used to investigate the TIEG
expression in various organs. In general, this method is a
highly sensitive and speci?c technique, but sometimes the
results could be misleading at speci?c conditions. For
example, a high-level expression in a small subset of cells
or cell types in a particular tissue could be underestimated, or the transcriptional changes might not be evident in the tissues yet overampli?cation could be
unappreciated by the qRT-PCR. Therefore, a whole-mount
in situ hybridization approach may be more appropriate
in this case (i.e., at early stages of embryogenesis).
Taken together, the expression of TIEG1 and TIEG2 is
speci?c in different organs yet varied with different developmental time points. Their dynamic changes of expression during murine development are consistent in most
organs except in the heart and muscle tissues, which indicate a compensation of functions in the TIEG family. Further investigations would be necessary to clarify this
issue and their roles in murine organogenesis.
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development, tieg1, change, tieg2, mouse, transcription, dynamics, tissue
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