ARTICLE |
Correspondence to: Markku PeltoHuikko, Dept. of Developmental Biology, Medical School, FIN-33014 Tampere University, Finland. E-mail: blmapel@uta.fi
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Summary |
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Aint was originally identified on the basis of its interaction in vitro with the aryl hydrocarbon nuclear receptor translocator (Arnt). Arnt is a common heterodimerization partner in the basic helixloophelix (bHLH)-PER-ARNT-SIM (PAS) protein family and is involved in diverse biological functions. These include xenobiotic metabolism, hypoxic response, and circadian rhythm. In addition, Arnt has a crucial role during development. Aint is a member of a growing family of transforming acidic coiledcoil (TACC) proteins and is the murine homologue of human TACC3. Here we report the spatiotemporal expression of Tacc3 mRNA and protein in embryonic, postnatally developing, and adult mouse tissues using in situ hybridization and immunocytochemistry. Tacc3 mRNA was highly expressed in proliferating cells of several organs during murine development. However, the only adult tissues expressing high levels were testis and ovary. Immunocytochemistry revealed that Tacc3 is a nuclear protein. Our results suggest that Tacc3 has an important role in murine development, spermatogenesis, and oogenesis. (J Histochem and Cytochem 51:455469, 2003)
Key Words: nuclear protein, in situ hybridization, immunocytochemistry, nervous system, immune system, respiratory tract, genitourinary tract, alimentary tract, maskin, d-TACC, AZU-1
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Introduction |
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ARNT interacting protein (Aint), also now referred to as transforming acidic coiledcoil protein 3 (Tacc3), is a recently discovered protein that has been shown to interact with the aryl hydrocarbon receptor nuclear translocator protein (ARNT) in vitro (
Although Tacc3 was recently cloned from a day 17 mouse embryo cDNA library as a result of search for novel ARNT interacting proteins, it is not a member of the bHLH/PAS protein family (), indicating that Tacc3 may have a role in ARNT signaling pathways. The PAS domain of ARNT mediates the interaction with Tacc3. In addition, transient transfection experiments revealed that Tacc3 augments the transcriptional response to hypoxia in the Hif-1
signaling pathway via the hypoxia response element (HRE) (
Tacc3 belongs to a new and growing family of coiledcoil proteins and is the mouse homologue of TACC3 cloned from human (
Recent studies suggest that the TACC proteins are a conserved family of centrosome- and microtubule-interacting proteins (
Tacc3 interacts in vitro with ARNT, ARNT2 and, to a lesser degree, with Sim2, and these proteins have developmental importance (
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Materials and Methods |
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In Situ Hybridization
In this study we used embryonic (E9E17), 36-hr, 3-, 8-, and 14-day-old and adult NMRI mice. Embryos and tissues were frozen on a block of dry ice and sectioned with a Microm HM-500 cryostat to serial 14 µm thick sections, thawed onto polysine (MenzelGläser; Hamburg, Germany) glasses and stored at 20C until used.
In situ hybridization was carried out as previously described by -[33P]-dATP (DuPontNEN; Boston, MA) to a specific activity of 109 cpm/µg using terminal deoxynucleotidyltransferase (Amersham; Poole, UK). The sections were briefly air-dried at room temperature before hybridization. Hybridization was performed in a humidified chamber at 42C for 18 hr with 5 ng/ml of the probe in a mixture containing 4 x SSC (1 x SSC = 0.15 M NaCl, 0.015 M sodium citrate), 50% formamide, 1 x Denhardt's solution (0.02% polyvinyl-pyrroline, 0.02% bovine serum albumin, and 0.02% Ficoll), 1% sarcosyl, 0.02 M phosphate buffer (pH 7.0), and 10% dextran sulfate. After hybridization the sections were washed four times at 55C in 1 x SSC for 15 min each and then left to cool for 1 hr at room temperature. The sections were rinsed in distilled water, dehydrated with 60 and 90% ethanol, and air-dried. Thereafter the sections were covered with Kodak MR5 autoradiography film (Kodak; Rochester, NY) and exposed at -20C for 3060 days. The autoradiography films were developed using LX24 developer and AL4 fixative (Kodak). Alternatively, the sections were dipped in NTB2 emulsion (Kodak) diluted 1:1 with distilled water and exposed at 4C. After 6090 days of exposure, the sections were developed with D19 developer (Kodak), fixed with G333 fixative (Agfa Gevaert; Leverkusen, Germany). The sections were counterstained with hematoxylineosin and examined with a Nikon FXA microscope equipped with epipolarization and brightfield optics and a PCO Sensicam digital camera (PCO; Kelheim, Germany). Autoradiographs were digitized with a Nikon Coolscan II filmscanner. Images were processed using Corel Draw software and printed with a Hewlett Packard 995c printer.
Immunohistochemistry
For immunocytochemistry, whole embryos (E9, E13, and E16) and tissues of 2-day-old (P2) mice were fixed by immersion in the 4% paraformaldehyde in PBS for 36 hr. The tissue samples were cryoprotected with 15% sucrose in PBS, frozen with carbon dioxide, and 10-µm sections were cut. The embryos were embedded in paraffin, cut into 5-µm sections, and deparaffinized. Endogenous peroxidase activity was inhibited by immersing the sections in 0.5% hydrogen peroxide in PBS for 20 min. A rabbit polyclonal antibody was raised against a peptide, (VTFQTPLRDPQTHRILSP, hTACC3 amino acids 5572; accession number NM006342 and AF156934 for mouse Tacc3) designed to detect both hTACC3 and mTacc3 and purified by passage over a CNBr-Sepharose 4B column (
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Results |
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Tacc3 mRNA Expression
In situ hybridization analysis of Tacc3 mRNA during embryonic and postnatal development and in adult mouse revealed a tightly regulated expression pattern in different organ systems. Tacc3 mRNA was detected at all time points studied in distinct organs, but the expression was most widespread throughout various tissues and at the highest level during embryonic days E11, E13, and E15. In some organs, the expression continued postnatally. However, in adult mouse high amounts of Tacc3 mRNA were present only in testis and ovary and lower levels were detected in thymus and spleen. (Table 1 and Table 2)
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Nervous System.
At the initial stages of prenatal brain development, at E9 and E10, strong expression of Tacc3 mRNA was seen in the rapidly growing primary proliferative matrix, the neuroepithelium. The neuroepithelium is almost the only component of the developing nervous system at this time and gives rise to all neural elements of the brain (
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Digestive System. In the alimentary tract, Tacc3 mRNA was expressed strongly in most of the hepatic parenchymal cells from E11 to E15, whereas later no signal could be detected (Fig 1b1f, Fig 3c, and Fig 3d). In all parts of the intestines, signal was seen both in mucosa, including epithelial cells, and in the muscular layer (Fig 1c, Fig 1g, Fig 3a, Fig 3e, and Fig 3f). The intestinal expression was high at E11 and E13, weak from E15 to postnatal day 1.5, and undetectable at P8, P14, and adult. In esophagus, Tacc3 mRNA was seen from E13 to P1.5 in the mucosa and muscular layer (Fig 3h). At E13 and E15 there was a signal in the tongue epithelium and muscle, while at E17 and P1.5 the expression was restricted to the epithelium (Fig 1c, Fig 1e, and Fig 1g). In the oral cavity, Tacc3 mRNA was seen from E13 to E17. In tooth, the expression could be observed from E13 to P1.5. The signal was seen in odontoblasts, inner and outer enamel epithelium, and in stratum intermedium (Fig 4c). Salivary gland showed low to moderate levels of Tacc3 mRNA from E15 to P1.5 (Fig 3b).
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Respiratory System. Tacc3 mRNA was expressed at a moderate level in nasal process at E11 (Fig 1b). In lung, the signal could be seen from E11 to E17 (Fig 1c, Fig 1d, and Fig 3g). At E13 the expression was strong, but subsequently it diminished and no signal could be detected postnatally. Tacc3 mRNA was seen both in lung mesenchymal and bronchial epithelial cells and in all layers of the pharyngeal, laryngeal, and tracheal (from E13 to E17) walls (Fig 3h).
Genitourinary System. Tacc3 mRNA was abundant in the primitive cortical region of kidney at E13 and E15, and weak expression was also seen in the medullary region (Fig 1e and Fig 4f). From E17 to P3 the signal was moderate, at P8 weak, and by P14 the expression had ceased. In urinary bladder, weak to moderate signal could be seen from E13 to P1.5 (Fig 1g). The expression was strongest in the muscular layer and the transitional epithelial cells were also positive, whereas the lamina propria was negative. The genital tubercle was strongly positive at E13 (Fig 1c) and the urethra was positive at E15. In testis, a weak signal for Tacc3 mRNA could be detected from E17 to P3. Thereafter, the expression gradually increased and reached a very high level in adult testis. Most of the seminiferous tubules exhibited a strong signal in adult. The strongly positive cells were primary and secondary spermatocytes and a lower signal was seen in early round spermatids (Fig 4j, Fig 4k, and 4l). The germ cells at earlier stages of development, Sertoli cells, and interstitial Leydig cells were negative. In ovary, moderate expression was seen in the interstitial cells and germinal epithelium at the age of 1 and 2 weeks and subsequently the expression diminished to nondetectable levels. Strong expression was observed in oocytes of primordial, primary, and secondary follicle stages at the age of 1 and 2 weeks and in adult (Fig 4n4p). A weak expression was seen also in granulosa cells of follicles at the same stages. Ovary was not studied during embryonic development.
Cardiovascular System. From E11 to P1.5, Tacc3 mRNA was expressed weakly in heart muscle cells and from E13 to P1.5 in the walls of large vessels such as the aorta (Fig 1c).
Lymphatic System. In thymus, very strong expression was seen from E13 to P1.5 (Fig 1g, Fig 1h, Fig 4g, and Fig 4h). During embryonic development the signal appeared in both medullary and cortical thymocytes. Postnatally, Tacc3 mRNA was located abundantly in the thymocytes of the outer cortex and a weak signal was seen also in the medulla. After P1.5, the expression declined. However, low levels were still observed in adult. In the spleen, Tacc3 was expressed both in the white and red pulp from E17 to P3 and low signal was present in the red pulp in adult (not shown).
Integumentary System. In skin, we found Tacc3 mRNA as early as E13, and the expression continued throughout embryonic development and could still be seen in the newborn mouse but not afterwards. The signal was particularly strong in the epidermis and in the hair follicles and vibrissae in the dermis (Fig 4i).
Musculoskeletal System. In somites, clear expression was observed at E10 (not shown). In limb bud, moderate expression could be seen at E10 and E11 (Fig 1b, Fig 4a, and Fig 4b). The branchial arches, which later form the chin, upper jaw, part of the auditory ossicles and hyoid bone, were positive at E11 (Fig 1b). Tacc3 mRNA was found in the mesenchyme adjacent to the primordial bones (in limbs shown in Fig 1d and Fig 1f), in the developing ligaments, and in intervertebral discs (Fig 4d and Fig 4e) from E13 to E17. In the developing muscles there was a clear expression from E13 to E17 (not shown).
Organs of Special Sense. In developing eye, Tacc3 mRNA expression was observed from E13 onwards and the expression was still detectable at P14, although absent in the adult (Fig 1d, Fig 1f, and Fig 2m2r). The mRNA was located in the inner nuclear layer of retina (Figure 2l). In the developing inner ear, the expression was seen at E13 and E15 in mesenchymal cells (Fig 1d, Fig 1f, and Fig 2j), and by E17 the expression had ceased. The expression was detected in olfactory epithelial cells from E13 to P1.5 (Fig 1c and Fig 2k).
Endocrine System. In thyroid gland, Tacc3 mRNA expression was seen at E17 (not shown). Weak expression was detected in adrenal gland at E15 and postnatally (P1.5) (not shown). Low expression was seen in pituitary from E13 to P1.5 (not shown).
Brown Fat. Brown fat showed low expression of Tacc3 mRNA at E17 and later was negative (Fig 1g).
Placenta and Fetal Membranes. We studied placenta at E9 and E10. There was a clear signal in all layers of placenta: in the chorionic plate, the labyrinth region, in spongiotrophoblasts, and more weakly in decidual cells on the maternal side (not shown). The giant trophoblasts were weakly positive. In fetal membranes, moderate expression was seen in yolk sac (not shown).
Tacc3 Immunoreactivity in Mouse Embryos and Postnatally
We studied Tacc3 immunoreactivity (IR) during murine development at embryonic days 9 (E9), 13 (E13), and 16 (E16) and 2 days after birth (P2). Tacc3 IR was nuclear and often localized in a distinct punctate pattern. The antibody gave cytoplasmic staining in some cells. However, this staining could not be abolished by presaturation with the peptide used for immunization, thus indicating nonspecific signal.
On the embryonic side of the placenta, protein expression was detected in the cells of the chorionic plate, labyrinthine part, and in spongiotrophoblasts of the basal layer (Fig 5a). In trophoblast giant cells, Tacc3 was localized to distinct points in the nucleus (Fig 5b). The staining was seen in nuclei of endothelial cells of the placental vessels. Tacc3 was expressed in yolk sac and amnion (Fig 5c).
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Tacc3 IR could be detected widely in mesenchymal cells at E9. In the neuroepithelium of the neural tube, most of the neuroblasts expressed Tacc3 (Fig 5d). The epithelium of developing intestinal canal and the surrounding mesenchymal cells were also labeled at E9.
At E13, the most intense immunoreactivity in the CNS was seen in the proliferating neocortical neuroepithelium (Fig 5e). Tacc3 IR was also detected in the nuclei of the neuroblasts of differentiating field. A weaker reaction was also observed in striatial, rhinencephalic, hippocampal, pallidal, tegmental, and tectal neuroepithelium and in differentiating field of thalamus, hypothalamus, and spinal cord. At this time, the cerebellar neuroepithelium appeared negative. No labeling was detectable in the dorsal root ganglia.
The majority of the hepatocytes exhibited Tacc3 IR at E13. The staining was moderate and located in the nucleus. At the same time, the intestinal epithelia did not express the protein, whereas weak staining was seen in the muscle cells of the intestinal wall. Similarly, the nuclei of pancreatic acinar cells were negative and the mesenchymal cells were weakly positive. Bronchial epithelium did not show any Tacc3 IR, whereas weak staining was observed in the mesenchymal cells of lung. In the genital tubercle, the epithelial cells covering the tubercle exhibited strong Tacc3 IR. In heart, weak staining was observed in the nuclei of heart muscle cells. The nuclei of endothelial cells of the vessels were stained. In thymus, a large number of cells were labeled. In the segmental interzone of backbone, future intervertebral disc, the nuclei exhibited weak dotted staining. In olfactory epithelium, weak nuclear staining was seen.
At E16, intense immunoreactivity for Tacc3 was detected in neuroepithelium and especially in the subventricular zone surrounding the lateral ventricles (Fig 5j). The nuclei of neuroblasts in differentiating fields of cerebral hemispheres exhibited weak labeling. In cerebellar hemispheres, moderate nuclear staining was observed in differentiating field (Fig 5i). At this stage, stained nuclei could be seen in both the cerebellar neuroepithelium and the external germinal layer. The ependyma of the choroid plexus was also positive. In spinal cord the neuroblasts displayed Tacc3 IR (Fig 5o).
Expression in the digestive system changed between E13 and E16. The intestinal epithelium expressed Tacc3 protein at E16 (Figure 5l), as did the pancreatic acinar cells (Fig 5m). The nuclei of muscle cells of the intestinal wall were also stained. Most of the cells in the liver expressed Tacc3 protein (Fig 5i). In salivary gland, both epithelial and mesenchymal cells were stained. The bronchial epithelial cells and mesenchymal cells of lung exhibited moderate Tacc3 IR (Fig 5g). The nuclei of endothelial cells of vessels (Fig 5f) and muscle cells of heart continued to express Tacc3 protein at E16. Moderate labeling was seen in thymocytes. The nuclei of striated muscle cells showed strong immunoreactivity (Fig 5h). In eye, moderately stained nuclei were observed in the inner nuclear layer of retina (Fig 5n). Nuclear staining was also seen in the single cells of cochlear epithelium of the inner ear and in brown fat and thyroid gland.
Postnatally, at P2 (2 days after birth), Tacc3 IR was observed widely in cerebral and cerebellar sections. In cerebellum, strong staining was observed in the nuclei of cells of the external germinal layer, in agreement with the in situ hybridization results. Separate stained cells were also seen in differentiating field (Fig 6d). The cerebral areas with strong Tacc3 IR included thalamic nuclei, hippocampus, meninges (arachnoid and pia mater), and ependyma. In eye, the most intensively stained cells were still the neuroblasts of the inner retinal layer. However, positive cells were also seen among the neuroblasts of the outer nuclear layer. Immunoreactivity was observed in corpus ciliare and epithelial cells of Hardenian glands. In peripheral nerves, the nuclei of Schwann cells were positive.
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In small intestine, Tacc3 was located in the nuclei of epithelial cells, cells of lamina propria, and muscle cells. In liver, a minority of hepatocytes were weakly positive, and moderately stained granulocytes and lymphocytes were also detected. In bile duct and gallbladder, the columnar epithelial cells showed strong Tacc3 IR (Fig 6a). The antibody continued to display strong staining in the pancreatic acinar cells. In kidney, labeled nuclei were seen in the epithelium of collecting tubules and loops of Henle, in both cortex and medulla. In glomeruli, the nuclei of podocytes were stained. Transitional epithelial cells of the renal pelvis expressed Tacc3 intensely (Fig 6b).
Tacc3 was seen postnatally in thymus and spleen. Tacc3 IR was strong in cortical thymocytes of the outermost layers of cortex (Fig 6c). Epithelialreticular cells and thymocytes in medulla were also weakly stained. In spleen, some lymphocytes were moderately stained. In skin, the basal layer of epidermis, hair follicles, and the striated muscle cells expressed Tacc3. The nuclei of adipocytes were positive (Fig 6e).
At P2, labeling was seen in the epithelial cells of endometrium and the smooth muscle cells of myometrium of the uterus (Fig 6f). Both ovary and testis expressed Tacc3 IR at this point (Fig 6g and Fig 6h). In ovary, strong labeling was evident in oocytes, granulosa cells of primordial follicles, interstitial cells, and cells of the germinal epithelium. In testis, the strongly stained cells included Sertoli cells, primitive germ cells, interstitial cells, peritubular cells, and fibroblasts of the tunica albuginea.
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Discussion |
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The present study describes the expression of Tacc3 mRNA during embryonic and postnatal development and in adult mice to shed light on the possible functions of Tacc3 during development and in adult tissues. Immunocytochemistry was performed at certain developmental time points to show Tacc3 protein expression. Previous studies have shown the importance of Arnt and Arnt2 in development (reviewed by signaling pathways, which are known to be crucial for normal development (
Expression of Tacc3 was detected in tissues of endodermal, ectodermal, and mesodermal origin. The expression in the CNS and in peripheral organs of mouse is highest and most widespread during fetal development from E13 onwards and continuing to 1.5 days after birth. This period of mouse development is the time of most active proliferation and differentiation in many organs. Because the expression of Tacc3 is associated with regions of rapid proliferation, it can be suggested that Tacc3 has a role in cell proliferation during mouse development. This is supported by studies suggesting a role for Tacc3 in interacting with microtubules during mitosis (
In the CNS, the development of a properly functioning neural network requires coordinated birth, migration, and death of neurons. The expression of Tacc3 mRNA in the proliferating neuroepithelium of neural tube and later in primary and secondary germinal matrices surrounding ventricles and in external granular layer of cerebellum, at the time when proliferation of neuronal cells occurs, suggests an important role for Tacc3 in birth of neural cells. Tacc3 IR was also seen in differentiating neurons, although at lower levels. When migration and further differentiation of neurons occur after the cells have left the germinal matrices, there is a downregulation of Tacc3, also supporting the role for Tacc3 at a temporally limited period of proliferation and differentiation. Current studies (Sadek et al. unpublished) have shown an upregulation of Tacc3 during early differentiation of PC12 cells into neurons and NIH 3T3-LI into adipocytes, and the levels diminish as the cells become terminally differentiated. Similarly, Tacc3 has been shown to be highly expressed during proliferation and at low level during differentiation (
It is interesting that Tacc3 is expressed highly and simultaneously with Hif-1 in the neuroepithelium of neural tube and that Hif-1a-/- embryos manifested failure of neural tube closure with cystic degeneration and prolapse of the neural folds at this time (
Tacc3 was expressed in several peripheral organs during embryogenesis. For example, in endoderm-derived hepatocytes, expression is high at the time of active proliferation. At E11, when expression starts, the size of the liver rapidly enlarges several-fold as the hematopoietic activity is transferred to liver from the yolk sac and as it matures functionally in several ways (reviewed by
In contrast to the other organs studied, Tacc3 mRNA levels in testis were low during prenatal and early postnatal development. However, when the mice matured and became fertile, Tacc3 mRNA levels increased remarkably. Tacc3 mRNA was highly expressed in primary spermatocytes and secondary spermatocytes, which are going through first and second meiotic divisions. High expression of TACC3 has also been detected in human testis with Northern analysis and immunocytochemistry (
In conclusion, the expression of Tacc3 is associated with regions of rapid proliferation, which suggests that it has a role in cell proliferation during normal mouse development. In addition, the high levels of Tacc3 during spermatogenesis and oogenesis provide evidence for a role in these pathways in the adult. Further studies will clarify the exact role of Tacc3 in different tissues.
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Acknowledgments |
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Supported by the Medical Research Fund of Tampere University Hospital, the Research and Science Foundation of Farmos, the Finnish Medical Foundation, and the Swedish Cancer Fund.
We thank Ulla-Margit Jukarainen and Riika Salmela for competent technical assistance. We thank Dr M. Tujague for his help with antibody preparation and testing.
Received for publication September 9, 2002; accepted December 12, 2002.
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