ARTICLE |
Correspondence to: Markku T. PeltoHuikko, Dept. of Developmental Biology, Medical School, Tampere University, FIN-33014 Tampere University, Finland. E-mail: blmapel@uta.fi
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Summary |
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The basic helix-loop-helix (bHLH-PAS) proteins aryl hydrocarbon receptor nuclear translocator (Arnt) and Arnt2 are transcriptional regulators that function as dimerizing partners for several bHLH-PAS proteins and also some nonrelated partners. They are involved in various biological functions, including regulation of developmental genes. In earlier studies, the developmental expression of Arnt was reported to be almost ubiquitous, whereas Arnt2 expression has been shown to be more limited, comprising neuronal tissues as the main site of expression. Here we provide a detailed description of the expression of Arnt and Arnt2 mRNA in mouse tissues during embryonic and early postnatal development. Arnt and also Arnt2 transcripts, in contrast to earlier reports, are shown to be expressed more widely during development yet show a temporally and spatially specific pattern. (J Histochem Cytochem 51:4154, 2003)
Key Words: in situ hybridization, nervous system, immune system, respiratory tract, genitourinary tract, alimentary tract, endocrine organs, lymphatic organs, musculoskeletal system
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Introduction |
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ARYL HYDROCARBON NUCLEAR TRANSLOCATOR (Arnt) and Arnt2 are transcriptional regulators and members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) protein family (
Arnt and Arnt2 as bHLH-PAS proteins share a conserved sequence structure. The dimerization interface between Arnt and Arnt2 and other bHLH-PAS proteins is provided by PAS and HLH motifs (
Arnt has a central role as a common heterodimerization partner in this family. Interaction with Arnt is a necessity for the ligand-activated aryl hydrocarbon receptor (AhR) to be able to bind to the regulatory DNA sequence XRE (xenobiotic response element) and to mediate biological responses to carcinogenic and toxic environmental chemicals (, and they bind together to HRE (hypoxia response element) of genes responsible for the adaptation to oxygen deprivation (reviewed by
Drosophila single-minded (SIM), a bHLH-PAS protein regulating central nervous system midline cell development (
Arnt mRNA expression is extensive during murine embryonic development (
Arnt2 is a close structural homologue of Arnt (63% identical) and can bind to DNA as a heterodimer with AhR, Hif-1, and Sim and can also homodimerize in vitro (
Homozygous Arnt2 gene knockout mouse embryos die perinatally and exhibit impaired hypothalamic development, similar to those of bHLH-PAS gene Sim1 knockout mice, concordant with the hypothesis that Sim1 and Arnt2 interact in vivo (
Although the number of known related and nonrelated proteins capable of heterodimerization with Arnt and Arnt2 is increasing, we report a detailed distribution of Arnt and Arnt2 mRNA in murine embryonic and postnatal tissues to understand better the in vivo interaction possibilities.
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Materials and Methods |
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In this study we used embryonic (E9-E17) and 36-hr-old (P1.5) NMRI mice (E0=day of conception). Embryos and tissues were frozen on a block of dry ice and cut with a Microm HM-500 cryostat to serial 14-µm-thick sections, thawed onto polysine (MenzelGläser; Braunschweig, Germany) glasses, and stored at -20C until used. At least three embryos for each time point studied were sectioned throughout and adjacent sections from five to ten different levels were used in hybridizations.
In situ hybridization (ISH) was carried out as previously described by -33P]-dATP (Du PontNEN; 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 (RT) before hybridization. Hybridization was done in a humified 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 RT. The sections were rinsed in distilled water, dehydrated with 60% and 90% ethanol, and air-dried. Thereafter the sections were covered with Kodak MR autoradiography film (Kodak; Rochester, NY) and exposed at -20C for 5060 days. The autoradiography films were developed using LX24 developer and AL4 fixative. Alternatively, the sections were dipped in NTB2 emulsion (Kodak), diluted 1:1 with distilled water, and exposed at 4C. After 60 days of exposure the sections were developed with D19 developer (Kodak), and 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.
The probe sequences exhibited less than 60% similarity to all known sequences in the GenBank database. All probes gave similar expression results when used separately and were usually combined to intensify the hybridization signal. As a control for specificity of ISH, several probes for nonrelated mRNAs with known expression patterns and with similar length and GC content were used as controls. Results with probes to sperm-specific thioredoxin (
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Results |
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Arnt mRNA Expression
ISH analysis showed the temporally and spatially specific expression of Arnt. Arnt was very widely expressed during mouse embryonic and early postnatal ontogeny (Fig 1; Table 1 and Table 2). The expression of Arnt could be detected in a variety of cell types of endodermal, ectodermal, and mesodermal origin.
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Nervous System. Arnt mRNA expression was widely seen in the central nervous system (CNS) during embryonic and early postnatal development. Expression was already strong at E9 and E10 in the neuroepithelium of the neural tube, which is the source of all neural elements of the brain and spinal cord (Fig 1d). Strong expression was seen later in the proliferating periventricular primary neuroepithelial cells (Fig 1a, Fig 1b, and Fig 1e). As development advances, neuron proliferation occurs in the secondary germinal matrices, and expression was seen in these areas. Arnt mRNA was also expressed in the migrating cells of differentiating fields of the brain and spinal cord. However, the intensity of expression had clearly declined to a weak or moderate level when the cells had switched to the postmitotic state and started their migration and differentiation. This type of expression was clearly seen in the septum, for example, where expression was strong at E13 and E15 in the septal neuroepithelium, moderate at E15 and E17 in the septal subventricular zone, and weak at P1.5 in the differentiating field. The neuroblasts and neurons of the dorsal root ganglia expressed Arnt mRNA at a high level from E13 to P1.5 (Fig 2j). A more detailed distribution of Arnt mRNA in various regions of the nervous system is reported in Table 1.
Digestive System. Arnt mRNA was detected throughout the alimentary canal, from the oral cavity to the anal canal, between E9 and P1.5. In the esophagus, stomach, and intestines expression was seen in the mucosa, including the epithelial cells, submucosa and the muscle layer (Fig 1e, Fig 1f, and Fig 2a). In the tongue, moderate expression was observed from E13 onwards until P1.5 (Fig 1b, Fig 1e, Fig 1f, and Fig 1h). In the epithelial cells, expression was stronger than in the muscle cells. In the submandibular salivary gland expression was seen at E17 and P1.5 in both the glandular and the mesenchymal cells (Fig 1f and Fig 1h). In the liver, strong expression was observed from E11 to E15, but by E17 the expression had clearly diminished (Fig 1a1c and Fig 1e). Most of the hepatocytes were positive and there was also a signal in the mesothelial cells of the liver capsule (Fig 2a). Arnt mRNA was expressed in the molar and incisor teeth at a moderate level at E17 and P1.5 (Fig 1h). No earlier stages of developing teeth were studied. Arnt mRNA was seen in the odontoblasts, both inner and outer enamel epithelium, and in the stratum intermedium (Fig 2c).
Respiratory System. Arnt mRNA was expressed in the nasal process at E11 at a moderate level (Fig 1a). In the lungs, the expression of Arnt was strong at E13 and moderate thereafter until E17 (Fig 1b, Fig 1c, Fig 1e, and Fig 1f). Arnt mRNA was indicated both in the bronchial epithelial cells and in the future parenchymal cells (Fig 2d). The trachea was studied at E17 and there were labeled cells in both the epithelium and the mesenchyme (Fig 1f).
Urinary System. In the primitive kidney, Arnt mRNA was expressed more abundantly in the cortical region than in the medullary region. The expression in the kidney was strong at E13 and moderate still at P1.5 (Fig 1e). In the urinary bladder, moderate expression was observed from E17 to P1.5 (Fig 1f). The signal was most intense in the muscular layer, but mRNA was also detected in the transitional epithelial cells. In the genital tubercle, there was a strong signal at E13 (Fig 1b). In the urethra expression was seen at E15 and E17 (not shown).
Cardiovascular System. Low levels of Arnt mRNA were seen in the heart muscle cells from E11 to P1.5 (Fig 1e and Fig 1f) and in the walls of big vessels, such as the aorta, from E13 to P1.5 (Fig 1e).
Lymphatic System. In the lymphatic system, the thymocytes of both the cortical and medullary regions of the thymus were moderately labeled from E13 to P1.5 (Fig 1f and Fig 1h). In the spleen, expression was observed at E17 and P1.5 (not shown).
Integumentary System. In the skin, Arnt mRNA was observed at a moderate level from E13 to P1.5 (Fig 1f and Fig 2e). The signal was located in the epidermis and hair follicles and vibrissae in the dermis.
Musculoskeletal System. There was clear expression of Arnt mRNA at E11 in the limb bud, strong expression at E13, and detectable expression in the limbs until E17 (Fig 1c, Fig 1e, and Fig 1f). In the developing bones, especially in the mesenchyme surrounding the bones (Fig 1b and Fig 2f), there was strong expression at E13 and E15 and weak expression at E17. In the muscles, expression was observed at E13 and E15 (not shown).
Organs of Special Sense. In the eye, Arnt mRNA was located in the inner and outer nuclear layers of the retina (Fig 1c, Fig 1g, and Fig 2g). Expression in the eye was strong from E13 to P1.5. In the developing inner ear, moderate to weak expression was seen from E13 to E17 in the cochlear epithelial cells, mesenchyme, and also in the cartilage primordium of the petrous part of the temporal bone that surrounds the inner ear (Fig 1g and Fig 1h). Moderate expression was seen in the olfactory epithelial cells from E13 to P1.5 (Fig 1e, Fig 1f, Fig 1h, and Fig 2i).
Endocrine System. Strong expression was found in the adrenal cortex from E13 to P1.5 (not shown). The pituitary gland exhibited Arnt transcripts at a moderate level from E13 to P1.5 (not shown).
Brown Fat. Arnt mRNA was seen in the brown fat at E17 (Fig 1f).
Arnt2 mRNA Expression
The expression of Arnt2 during murine development differs clearly from that of Arnt, although they share several sites of expression (Fig 3; Table 3 and Table 4). Arnt2 mRNA is very strongly expressed in the developing nervous system on all the embryonic and postnatal days studied. Outside the nervous system the expression of Arnt2 mRNA is more limited than that of Arnt, and expression levels in the peripheral organs are generally lower than in the nervous system.
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Nervous System. Arnt2 mRNA expression was prominent in CNS through the embryonic period studied and 1.5 days postnatally (Fig 3; Table 3). The expression was mostly very strong and covered many but not all parts of the CNS. Expression was also seen in the mitotic cells of the neuroepithelium of the neural tube, periventricular primary neuroepithelium, and secondary germinal matrices as in the postmitotic migrating cells of the differentiating regions. No expression was observed in the non-neuronal areas such as the fiber tracts. No clear change in the intensity of signal was seen as the development of the neurons progressed during the embryonic period, but at postnatal day 1.5 the expression showed a tendency to decline in many regions of the CNS.
Expression was already very strong in the neuroepithelium of neural tube at E9 (Fig 3a, Fig 3b, and Fig 3d). High expression was observed in the cerebral cortex on all the days studied. At E17, separate layers of the cortical area exhibited different amounts of Arnt2 transcripts. The signal was strong in the neocortical neuroepithelium and the subventricular zone, weak in the differentiating field, and very strong in the cortical plate in the infra- and supragranular parts (Fig 3c, Fig 3j, Fig 4a, and Fig 4d). By P1.5, expression in the neuroepithelium and subventricular zone had weakened, whereas high expression in the cortical plate still remained (Fig 3j). No signal was seen in the molecular layer of the neocortex. The olfactory bulb, rhinencephalon, septum, and preoptic area all displayed high expression of Arnt2 mRNA. Very strong expression was found in the midbrain in the tectal and tegmental neuroepithelium, the tegmental differentiating field, and the differentiating fields of the superior and inferior colliculus (Fig 3d, Fig 3e, and Fig 3j). In the developing hippocampus at E11, expression was very strong, but at E13 and E15 expression clearly weakened until it became very strong again at E17 and postnatally both in the differentiating areas of the dorsal and ventral hippocampus, the subicular area, and the dentate gyrus (Fig 3j). In the basal ganglia, the pallidum, and striatum, high expression was found (Fig 3j). The thalamus and hypothalamus expressed Arnt2 mRNA very strongly during the embryonic period and strongly postnatally (Fig 3e, Fig 3g, and Fig 3j). In the pontine and medullary areas expression was high, except in the differentiating fields, where it diminished to a moderate level postnatally (Fig 3j). In the cerebellar neuroepithelium, where the Purkinje cells originate, expression was very strong or strong from E11 to E15 but had ceased by E17, as did the mitotic activity in this area (Fig 3d, Fig 3e, Fig 3g, and Fig 3h). In the Purkinje cell layer, expression was moderate at E17 and P1.5 (Fig 3g and Fig 3j). In the external germinal layer, where the birth and migration of the granule neurons occur later than in many other brain areas, a moderate expression of Arnt2 mRNA appeared at E17 and continued postnatally. In the differentiating areas of the cerebellum, weak expression was detectable only at E17. High expression was observed in the spinal cord (Fig 4c). Strong Arnt2 mRNA expression was discovered in the dorsal root ganglia from E13 to P1.5 and in the trigeminal ganglion from E13 to E17 (Fig 4n). The postnatal trigeminal ganglion was not studied.
Digestive System. In the tongue, moderate expression of Arnt2 mRNA was seen at E11. A weak signal was observed still at E17 but not later (Fig 3e, Fig 3g, and Fig 3i). The Arnt2 mRNA was localized in the muscle layer and connective tissue just beneath the epithelium of the tongue, whereas the epithelial cells did not express Arnt2 (Fig 4g). In the epithelial cells of the submandibular salivary gland, weak expression was observed at E17 (Fig 3i and Fig 4h). In the esophagus, Arnt2 mRNA could be detected from E13 to E17 (Fig 3j) (P1.5 was not studied), in the stomach and intestines from E11 onwards (Fig 3d, Fig 3e, Fig 3g, and Fig 3i). In the intestines, expression was seen in all layers, but it was at its strongest in the muscle cells of the tunica muscularis (Fig 4i). No Arnt2 mRNA could be detected at any stage in the liver (Fig 3d, Fig 3e, and Fig 3i). Weak to moderate expression was seen in the teeth at E15, E17, and P1.5 in the mesenchymal cells of the dental follicle (Fig 3i and Fig 4j).
Respiratory System. Strong expression of Arnt2 was discovered in nasal process at E11 (Fig 3d). In the trachea, expression was found at E13 and E17 in the epithelial and mesenchymal cells (Fig 3g). Both the epithelial and mesenchymal cells of the lung expressed Arnt2 from E11 to E17 but not postnatally (Fig 3e3g).
Urinary System. Arnt2 mRNA was expressed in the genital tubercle at E11 and E13 (Fig 3e). In the developing kidney, strong to moderate expression of Arnt2 was observed from E13 onwards and at 1.5 days after birth (Fig 3g). The expression was strongest in the epithelial cells of the primitive glomeruli. In the urinary bladder, the signal was seen in the muscular layer and the transitional epithelial cells at E17 and at P1.5 (Fig 3i). In the urethra, Arnt2 mRNA was discovered in all layers at E15 and E17 (not shown).
Cardiovascular System. No Arnt2 mRNA could be detected in the heart at any time in this study. In the walls of the large blood vessels, a weak signal could be detected at E15 and E17.
Lymphatic System. In the spleen, expression of Arnt2 was seen at P1.5 (not shown). The thymus was weakly positive at E17 and P1.5 (Fig 3i and Fig 3j).
Integumentary System. The epithelial cells of the most superficial layer of the epidermis expressed Arnt2 clearly at E17 and P1.5 (Fig 4k). The cells of the hair follicles and follicles of vibrissae were positive from E13 to E17 (Fig 3f).
Musculoskeletal System. Arnt2 mRNA was detected in the mesenchymal cells around the cartilage primordia of the developing bones of the limbs from E11 to E17 and the backbone from E13 to E15 (Fig 3e). At E17, weak expression was observed in the mesenchymal cells of the progress zone in the distal tip of the limb (Fig 3f and Fig 3h). The muscle cells expressed Arnt2 weakly at E13 and E15.
Organs of Special Sense. The inner nuclear layer of the retina expressed high levels of Arnt2 mRNA from E13 onwards (Fig 3c, Fig 3f, and Fig 3h). In the developing inner ear, the signal of Arnt2 mRNA was seen both in the cochlear epithelial and mesenchymal cells from E13 onwards (Fig 3h and Fig 4l). At E17 the signal was strong, but weak before and afterwards. In the olfactory epithelial cells, Arnt2 mRNA was detected from E13 to P1.5 (Fig 3i and Fig 3j). From E13 to E15 the signal was weak, at E17 strong, and at P1.5 weak again.
Endocrine System. In the adrenal medulla, the signal was strong at E13 and still at P1.5 (Fig 4m). The thyroid expressed Arnt2 at E17 (not shown). In the pituitary gland, large amounts of Arnt2 transcripts were detected from E15 to P1.5 (Fig 3e, Fig 3i, and Fig 3j).
Others. The brown fat was negative at all times.
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Discussion |
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In this study we report the expression of Arnt and Arnt2 mRNAs by ISH in the CNS and peripheral tissues during mouse fetal and early postnatal development. There are earlier reports of the expression of both Arnt and Arnt2 (
Arnt mRNA was widely expressed at all stages studied from E9 to postnatal day 1.5, in agreement with previous studies. However, the expression was not ubiquitous and it showed both temporal and spatial specificity. In some organs (certain brain areas, heart muscle, thymus, skin, retina, olfactory epithelium, adrenal gland, and dorsal root ganglion), expression was stable on all the days studied, whereas in some others the level of expression changed from strong to low or undetectable (tegmental neuroepithelium, liver, lung, bones, and muscles). In the same way as with Arnt, the expression of Arnt2 mRNA was temporally and spatially specific and could be detected at all the times investigated. Compared to the earlier studies that have reported Arnt2 gene transcripts being limited to the neuroepithelium, dorsal root ganglia, adrenal medulla, kidney, and the inner layer of the retina (
On a gross scale, the expression of Arnt mRNA in the CNS was weaker (although the intensity reached a strong level in several areas) but almost as extensive as that of Arnt2. The expression of both Arnt and Arnt2 could be seen in the same brain areas, often at the same time, but Arnt mRNA expression showed a tendency to decline as the development of the neurons progressed toward their differentiated state, whereas the levels of Arnt2 stayed mainly at a high level throughout the fetal period and also postnatally. No expression of either Arnt or Arnt2 mRNA was seen in the brain areas containing nerve fibers and glial cells, such as the corpus callosum. This was in agreement with the previous investigations (
The shared in vitro interaction partners of Arnt and Arnt2 also expressed in developing mouse CNS include HIF1- (
for brain development, which has been provided by Hif1-
knockout mice studies (
2/- embryos manifested neural tube defects. AhR has been detected in the mouse neuroepithelium at E10-13, but levels in the brain decreased as development progressed (
SIM is known as a master regulator of the Drosophila CNS midline development (reviewed by
Outside the CNS we were able to show many novel sites of expression for Arnt2 mRNA. For example, Arnt2 has not been previously found in the digestive system. In addition, we show expression in the branchial arch, tongue, salivary gland, stomach, intestines, and teeth. Both Arnt and Arnt2 transcripts were observed in these developing organs and therefore Arnt and Arnt2 may serve as dimerization partners for the same proteins. However, in the teeth they were expressed in different sites, suggesting that they function in dimer formation in separate areas and do not compete in the developing teeth. No Arnt2 transcripts were seen in the liver, where AhR signaling pathways are crucial for proper development, leaving Arnt as a candidate for interaction partner for AhR. No expression of Arnt2 mRNA was seen in the palate either, whereas it has been suggested that AhR and Arnt are important for normal palatogenesis (
Our report confirms the expression of Arnt2 transcripts in the lungs, as this remained unclear in the study of Jain and the co-workers (1998) where they reported low or undetectable expression in the lungs. We also report the nasal process and the trachea as novel sites of Arnt2 mRNA expression and these were sites of Arnt expression as well. In addition to the kidney, which has been reported earlier (
It has been suggested that Arnt2 is the candidate for the thymus defects of c112K deletion mice (
Further novel locations for both Arnt and Arnt2 transcripts are the skin, the hair follicles and the follicles of vibrissae. Arnt has previously been reported in the bones and muscles (
We found prominent expression of Arnt expression in the inner and outer nuclear (neuroblastic) layer of the retina and Arnt2 mRNA in the inner nuclear layer. These layers will later form the horizontal cells and the photoreceptor cells (outer nuclear layer) and the ganglion cells (inner nuclear layer). Taken together with the strong neuronal expression in the CNS, the retinal presentation of Arnt and Arnt2 transcripts is not surprising. The earlier results of expression in the eye differ from ours, as Arnt has been either weak or undetectable ( and AhR in the inner layer of the retina (
We found expression of both Arnt and Arnt2 mRNA in the olfactory epithelium and in the cochlear epithelial cells and surrounding mesenchyme of the inner ear, which was a new observation. The co-expression of Arnt and Arnt2 has been demonstrated in adrenal gland, which is derived from the neural crest (medulla) and mesoderm (cortex) (
In conclusion, we have described in detail the expression of Arnt and Arnt2 mRNA during embryonic and postnatal development of the mouse using ISH. We were able to confirm the earlier reported sites of strong expression and in addition could detect organs and tissues where Arnt and especially Arnt2 transcripts were revealed for the first time. Interestingly, we found that Arnt and Arnt2 are expressed in parallel in many tissues, where they may compete or substitute for common heterodimerizing partners, whereas in earlier reports the expression of Arnt2 has been thought to be very limited and Arnt almost ubiquitous. There are also tissues in which they are expressed separately referring to the discrete functions.
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Acknowledgments |
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Supported by the Medical Research Fund of Tampere University Hospital, Research and Science Foundation of Farmos, and the Finnish Medical Foundation.
We are grateful to Ulla Jukarainen and Riika Salmela for skillful technical assistance.
Received for publication January 23, 2002; accepted August 14, 2002.
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