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Keywords:

  • TIEG1;
  • TIEG2;
  • embryogenesis;
  • mRNA expression

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED

TGF-β-inducible early-response gene (TIEG) is a family of primary response genes induced by TGF-β, which are well recognized in regulating cellular proliferation and apoptosis. However, their expression profile 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 profile 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 specific 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 significantly 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 specific at various developmental stages. Anat Rec, 2010. © 2010 Wiley-Liss, Inc.

Transforming growth factor-beta (TGF-β) and other growth factors constitute a large family of multifunctional proteins, which are known to regulate various biological processes including cell growth, proliferation, differentiation, and apoptosis (Padgett et al.,1998; Chen and Meng,2004). They are capable to induce various 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-β signaling pathway is also capable to promote carcinogenesis via induction of epithelial-mesenchymal transition (Rane et al.,2006; Caja et al.,2007).

TGF-β-inducible early-response gene (TIEG) is a family of primary response genes induced by TGF-β and was originally identified 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 Krüppel-like family of transcription factors (Fautsch et al.,1998; Chrisman and Tindall,2003). TIEGs are involved in TFG-β signal transduction (Cook and Urrutia,2000) and are playing significant roles in regulating cell proliferation and apoptosis in various cell types (Tachibana et al.,1997; Ribeiro et al.,1999). Upon overexpression, TIEG1 enhanced TGF-β 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 identified. All of them contain three C2H2 zinc fingers 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-β1 treatment with similar induction time course (Cook et al.,1999; Hefferan et al.,2000b). Moreover, they have all been identified in mouse (Yajima et al.,1997; Fautsch et al.,1998; Wang et al.,2004), whereas only two of them, TIEG1 and TIEG2, are identified in human (Subramaniam et al.,1995; Cook et al.,1998). In general, TIEG2 shares 91% homology with TIEG1 within the zinc finger region (Cook et al.,1999), whereas TIEG3 shows 26 and 66% similarity to TIEG1 and TIEG2, respectively (Wang et al.,2004).

Recently, significant 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 significantly 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-β 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-β. The transcriptional level of TIEG1 was found significantly reduced in breast cancer, rendering it one of the most reliable markers to use with a sensitivity and specificity 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 caveolin-1 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-β (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-β that bridges the TGF-β signaling pathway with the apoptotic intracellular pathway (Wang et al.,2007).

Although TIEGs are well recognized to regulate cellular proliferation and apoptosis, their expression profile 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.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED

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 sacrificed 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 μg) was reverse-transcribed using the ImProm-II™ Reverse transcription system (Promega) according to the manufacturer's instructions.

Quantitative Real-Time PCR

The quantitation of mRNA was carried out using a real-time fluorescence detection method. Quantitative real-time PCR (qRT-PCR) was performed using SYBRs 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 fluorimetric 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 nonspecific 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 efficiency of reverse transcription. The primers used in this study are listed as follows: TIEG1 forward primer: 5′-GCT CAA CTT CGG CGC TTC TC-3′, reverse primer: 5′-ACT TCC AGT CGC AGC TCA TG-3′; TIEG2 forward primer: 5′-TCC CGA AGG AGG AAC TAT GT-3′, reverse primer: 5′-CCT GGG ATC TTC TTG GTT GT-3′; GAPDH forward primer: 5′-AAC ATC AAA TGG GGT GAG GCC-3′, reverse primer: 5′-GTT GTC ATG GAT GAC CTT GGC-3′. 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 final 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.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED

Tissue-Specific 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 figures) 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 specifically 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 significantly 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.

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Figure 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.

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Figure 2. Relative amounts of TIEG2 mRNA expression in different organs during murine development.

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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 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 significantly 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 significantly 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 significant 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.

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Figure 3. Dynamic change of TIEG1 mRNA expression in various organs during murine development.

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Figure 4. Dynamic change of TIEG2 mRNA expression in various organs during murine development.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED

In this study, the mRNA expression of both TIEG1 and TIEG2 was profiled 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-specific 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 final developmental stage of the cardiac and muscle cells. The findings of this study provide the basic understanding on the expression profile 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-β 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-β 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 long-term 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-β 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-β 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 fibrosis (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 TGF-β 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 significant 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-β-induced apoptosis, which strongly indicates that the TIEG is a downstream protein in the TGF-β-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-β 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 finger 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 exemplifies 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 specific technique, but sometimes the results could be misleading at specific 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 overamplification 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 specific 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.

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. LITERATURE CITED
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