Expression of the orphan receptor TR4 during brain development of the rat

Molecular Brain Research 77 (2000) 104–110 www.elsevier.com / locate / bres

Research report

Expression of the orphan receptor TR4 during brain development of the rat Hermien S.A. van Schaick a , Judith G.M. Rosmalen a , Sofia Lopes da Silva a , b a, Chawnshang Chang , J. Peter H. Burbach * a

Section of Molecular Neuroscience, Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands b George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology and Biochemistry, University of Rochester, Rochester, NY 14642, USA Accepted 15 February 2000

Abstract The orphan receptor TR4, member of the nuclear hormone receptor family, is related to the orphan receptors TR2, COUP-TFI and ARP-1, and was originally cloned from the adult rat brain. The latter two orphan receptors have been implicated in central nervous system (CNS) development. To investigate a possible role for TR4 in brain development, expression of TR4 was studied in rat embryos. At embryonic days 14.5 and 19.5, high expression of TR4 was found in the CNS, while low expression was detected throughout the embryo. In postnatal rats, TR4 was mainly expressed in the hippocampus and cerebellum, resembling the expression pattern found in adult brain. These data show that like COUP-TFI and ARP-1, expression of TR4 becomes restricted to distinct areas. In adult brain, TR4 is predominantly expressed in granule cells of both hippocampus and cerebellum. The data suggest a possible role for TR4 during proliferation and maturation of brain structures.  2000 Elsevier Science B.V. All rights reserved. Themes: Neurotransmitters, modulators, transporters, and receptors Topics: Receptor modulation, up- and down-regulation Keywords: Nuclear hormone receptor; Orphan receptor TR4; Brain development; Granule cells

1. Introduction Nuclear hormone receptors are ligand-activated transcription factors that regulate the expression of target genes by binding as monomer, homodimers or heterodimers to regulatory elements of these genes (reviewed in Ref. [21]). The family of nuclear hormone receptors also contains factors which are putative receptors for unknown ligands, named orphan receptors. This family comprises over 40 known members, several of which coordinate complex events involved in development, differentiation and physiological responses to diverse stimuli. In the *Corresponding author. Tel.: 131-30-253-8848; fax: 131-30-2538859. E-mail address: [email protected] (J.P.H. Burbach)

nervous system orphan receptors are thought to exert functions during brain development as well as in the functioning of the adult brain [18]. In invertebrates several specific functions have been delineated. For instance, the Drosophila melanogaster gene seven-up (svp) is required for the differentiation of the photoreceptor cells in the eye. Mutation in vivo of this gene leads to aberrant transformation of photoreceptor cells [22]. In Xenopus embryos, retinoic acid receptors (RARs) and retinoid X receptors (RXRs) have been implicated in the induction and early development of the nervous system, in particular in the anterior–posterior transformation of the developing central nervous system (CNS) [6,27]. In the nematode C. elegans, odr-7 is required for the function of one particular pair of chemosensory neurons [31]. While many orphan receptors are expressed in the

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vertebrate brain, little is known about their function. Recent data suggest a role in neurogenesis. For instance, transcription of both COUP-TFI and the closely related factor ARP-1 (COUP-TFII), the vertebrate homologs of the Drosophila seven-up gene, can be induced in P19 embryonal carcinoma cells (P19EC) by retinoic acid treatment resulting in the differentiation of P19 EC cells toward a neuronal phenotype [11]. COUP-TFI and ARP-1 [19,20,25], Nurr1 [12,37], Nur77 [29] and NOR1 [23] are all expressed in specific subsets of neurons in the developing nervous system, indicating that they regulate genes that are important for growth and differentiation in the vertebrate brain. Recently it appeared that the Nurr1 gene is essential for the development of mesencephalic neurons by inducing dopaminergic synthesis and maintaining cell survival [30,36], while SF-1 / ELP is essential for the formation of the ventromedial hypothalamic nucleus [10]. The patterns of expression in the adult brain and the mode of action of orphan receptors suggest, however, that these receptors can also be important regulators of genes in the mature CNS. It has been shown that orphan receptors such as Nur77 [29,37], Nurr1 [12], ERR1 [7], RZR [2,24], ROR [28], COUP-TFI and ARP-1 [19] are expressed in the adult brain with restricted and distinct expression patterns, which suggests different functional roles for each of them. The orphan receptor TR4, also named TAK1 and TR2R1, has been cloned from mouse brain, human and rat hypothalamus, prostate and testis cDNA libraries [5,9,13]. This orphan receptor is structurally most closely related to the previously identified orphan receptor TR2 [3,4] and belongs to a subfamily together with other receptors like COUP-TFI and ARP-1 [18]. Coding TR4 transcripts exist in splice variants, encoding TR4 protein differing in a 19 amino acid insertion in the N-terminus [5,33,34] and a third that produces a C-terminally truncated protein. The latter appeared to be rare. Both transcripts are expressed in both the central nervous system and peripheral organs. Transcripts have been found in low amounts in adrenal gland, spleen, thyroid gland, prostate and pituitary gland of rat and mouse. In testis, TR4 was most abundantly expressed in spermatocytes, whereas little expression was observed in other germ cells and somatic cells [9]. The adult rat brain displays significant hotspots of high expression: the habenula, the hippocampal pyramidal cells, and the granule cells of both the hippocampus and cerebellum [5]. It has been suggested that the high expression of TR4 is related to the proliferation state of the granule cell types in hippocampus and cerebellum and therefore may play a role during development of the CNS, or be related to a common regulatory function of TR4 in these cells. In view of a possible role for TR4 during neurogenesis and differentiation, the expression of TR4 was studied during rat brain development. The results show a wide expression at embryonic stages that becomes restricted during neuronal maturation.

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2. Materials and methods

2.1. Animals Wistar rats (150–250 g) at defined stages of gestation were decapitated and fetuses were rapidly removed from the uteri. Newborn rats were decapitated and brains dissected. For the in situ hybridization experiments whole embryos at embryonic days 14.5 (E14.5) and 19.5 (E19.5) and brains from newborn rats were quickly frozen in isopentane (Fluka Chemie, AG, Buchs, Switzerland) on an ethanol / dry ice mixture and stored overnight at 2808C. For the Northern blot analysis, embryos at stage E14.5 were divided into a head and body region. From embryos at stage E19.5, newborn and adult rats, brains were dissected and cortex, hippocampus and cerebellum isolated. Tissues were directly stored at 2808C until further use.

2.2. Probes for in situ hybridization and Northern blot analysis A 627-bp TR4 cDNA fragment spanning nucleotides 619–1246 according to Ref. [5] and a 304-bp cDNA fragment spanning nucleotides 1–304 were subcloned into the vector pGEM-7(Zf1) (Promega). For the in situ hybridization experiments sense and antisense RNA probes were generated by in vitro transcription with 1 mg of linearized plasmid DNA, 60 mCi [a- 35 S]UTP and RNA polymerase. Northern blots were hybridized with the 627bp TR4 cDNA fragment and a 1600-bp cDNA fragment of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Probes were labeled with [a- 32 P]dCTP using a random primed DNA labeling kit (Boehringer, Mannheim, Germany) according to the manufacturer’s protocol.

2.3. In situ hybridization The 16-mm cryostat sections were mounted on poly-Llysine-coated microscope slides and stored overnight at 2808C. Slides were placed at room temperature for 10 min and fixed in 4% paraformaldehyde in PBS for 5 min. In situ hybridizations were performed as described previously [19] with minor modifications. Hybridized sections were exposed for 3 days using hyperfilm B-max (Amersham, Buckinghamshire, UK). Later on sections were coated with Hypercoat Emulsion LM-1 RPN40 (Amersham), stored at 48C and developed after an exposure time varying from 4 to 8 weeks.

2.4. Northern blot analysis Total RNA was prepared by a single-step procedure using RNAzolEB (Cinna / Biotecx, Friendswood, USA) according to the manufacturer’s protocol. Samples of 30

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mg total RNA were run on a 0.7% agarose gel with 2.2 M formaldehyde, transferred to a nylon filter (Hybond N, Amersham, UK), and probed with a 32 P-labeled rat TR4 cDNA fragment overnight at 658C. Blots were washed in 23 SSC, 0.1% SDS and air-dried. Hybridization signals were analysed using a Fujix BAS 1000 bio-imaging analyzer system (Fuji, Germany).

3. Results

3.1. In situ hybridization The spatiotemporal expression of the TR4 gene in the developing nervous system was studied by in situ hybridization on transverse sections of rat embryos ranging from embryonic day 14.5 to newborn rats (P0.5), and by Northern blot analysis of tissues obtained at these developmental stages. For the in situ hybridization experiments two different probes were used derived from rat TR4 cDNA. The first probe included sequences encoding the DNA binding domain, the second probe was derived from the 59-end of rat TR4 cDNA. These probes did not

distinguish between the a1 and a2 splice variants of the TR4 gene [33,34]. The specificity of the hybridization signal was confirmed by using sense RNA probes synthesized from the same TR4 cDNA fragments, and the identity of the expression patterns obtained from the two antisense probes. Fig. 1A shows the expression of TR4 at embryonic day 14.5. Low levels of TR4 transcript were detected throughout the embryo, whereas relatively high levels of expression were found in the CNS. All neural structures were densely labeled. At E19.5, TR4 was still expressed widely in neural and non-neuronal structures (Fig. 1B). CNS expression was ubiquitous with highest levels in sublayers of the cerebral cortex, in particular the cortical plate and neuroepithelial / subventricular layers. Subcortical regions, including the developing striatum and subventricular zone and the developing hypothalamus, were also relatively most active in TR4 expression. Extra-neural expression was remarkably high in the thymus. More moderate expression was found in lung, submandibular gland, kidney (not shown) and intestine. None of the structures were labeled with a TR4 sense probe, indicating specificity of the in situ signals.

Fig. 1. Localization of TR4 orphan receptor transcripts in the developing rat embryo by in situ hybridization at embryonic days 14.5 (A) and 19.5 (B). At E14.5 expression is seen in the rhombencephalon (Rb), mesencephalon (Me) and telencephalon (Te). At E19.5, abundant expression is found in the cortex (Cx), thymus (Th), lung (Lu) and submandibular gland (Sm). The scale bar represents 3 mm.

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Fig. 2. Localization of TR4 transcripts in the brain of newborn rats by in situ hybridization. Autoradiograms of transverse sections at two different locations of the brain are presented. TR4 expression is most abundant in (A) the hippocampus (Hc) and present at lower levels in (B) the cortex (Cx). The scale bar represents 3 mm.

To investigate whether further restriction of TR4 expression could be detected in the developing brain, in situ hybridization experiments were also performed on brain sections of rats at the day of birth (P0.5) (Fig. 2). In newborn rats, TR4 expression in the brain was most abundant in the hippocampus, and present at lower levels in the cortex. This expression pattern resembled the pattern found in the adult brain (Fig. 3) [5]. While the adult cerebellum displays high expression of TR4, expression was still moderate in the cerebellum of newborn rats (results not shown).

3.2. Northern blot analysis Northern blot analysis was used to follow the course of TR4 expression in the CNS during development (Fig. 4). Total RNA from dissected tissues was examined on Northern blots hybridized with the 627-bp rat TR4 cDNA probe, followed by a GAPDH probe as an internal control. At E14.5, TR4 was more abundantly expressed in the head than in the body. These results confirmed the in situ hybridization data showing that the highest level of TR4 transcript was found in the CNS compared to other parts of

Fig. 3. Localization of TR4 transcripts in the adult rat brain by in situ hybridization on transverse sections. Wide expression is seen in hypothalamic, thalamic and cortical regions. Intense hybridization signals are found in cell layers of (A) the hippocampus (Hc) and (B) cerebellum (Cb). The scale bar represents 3 mm.

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Fig. 4. Northern blot analysis of TR4 orphan receptor mRNAs from rat embryos at developmental stages E14.5 and E19.5, brains of newborn (P0.5) and adult rats. A GAPDH probe was used as a control on the amount of RNA in each lane.

the embryo. From E19.5 onwards, TR4 expression levels were compared between cortex, hippocampus and cerebellum. At E19.5, the highest level of TR4 expression was detected in the cortex, whereas lower levels of expression were detected in the hippocampus (45%) and the cerebellum (30%). When comparing the results of E19.5, newborn rats (P0.5) and adult rats, the amount of TR4 transcript in the cortex decreased, by about 25% at P0.5 and 55% in adult rat, as estimated from Northern blot signals quantitated by phospho-imaging normalized to the GAPDH signal, whereas it increased in the cerebellum by about two-fold. In the hippocampus no changes in relative TR4 expression were observed.

4. Discussion From the present data it is concluded that during rat embryogenesis TR4 is widely expressed in tissues from all three germ layers, with the highest level of expression in the CNS and the thymus. At E14.5, TR4 is most prominently detected in the head region of the CNS. Notably, at E19.5 TR4 expression still overlaps with neuroepithelial and subventricular structures suggesting a role in neurogenesis. From stage E19.5 onwards the level of TR4 expression in the cortex decreases, whereas it increases in the cerebellum. In the brain of newborn and adult rats [5] high expression of TR4 is retained in granule cells of the hippocampus. Granule cells are small, densely packed

neurons that arise relatively late during brain development and undergo postnatal neurogenesis [1]. They have no direct functional properties in common. Since both the cerebellum and hippocampal granule cells show strong proliferation and maturation until late after birth, these results suggest a role for TR4 in the development of the nervous system. Outside the CNS, TR4 expression was found at high levels in the thymus at E19.5 and in adult rats, and in several tissues throughout the embryo, including lung, submandibular gland and kidney. The expression pattern in the trunk resembles the expression of ARP-1 in mouse embryos, which is characterized by diffuse expression throughout the embryo, with high levels in kidney and lung [11,20,25]. In the head region both TR4 and ARP-1 are expressed in the submandibular gland and the trigeminal ganglion. A significant feature of the developmental expression of TR4 is the temporal biphasic pattern characterized by the wide and abundant expression in the CNS during the phase of proliferation and maturation, followed by marked restriction to the specific and limited expression pattern found in the post-natal and adult brain. In this respect, the developmental regulation of TR4 expression resembles the orphan receptors COUP-TFI and ARP-1 [19]. In the developing CNS of mouse and Xenopus, both COUP genes are widely expressed with overlapping patterns [11,19,25,32]. At E11.5, COUP-TFI expression was predominantly found in the telencephalon and in the hindbrain, with weak expression in all neural tissues. High

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expression of COUP-TFI was found in the wall of all brain vesicles. At this stage ARP-1 expression largely overlapped that of COUP-TFI. At E14.5, expression of both genes became more restricted and ARP-1 expression only partially overlapped COUP-TFI expression. Common regions of expression included the posterior commissure and cerebellum. In the adult mouse, both COUP-TFI and ARP1 were found to be localized in distinct regions of the adult mouse brain [19]. COUP-TFI transcripts were predominantly detected in the rostral and caudal parts of the adult mouse brain, whereas ARP-1 expression was mostly restricted to the middle part of the brain. Expression of both COUP-TFI and ARP-1 was only detected in the ventral lateral thalamic nucleus. It has been suggested that both COUP-TFI and ARP-1 play important roles during development and differentiation of the CNS, including the specification of diencephalic neuromeres [11,19,20,25]. Interestingly, null mutation of the COUP-TFI gene results in perinatal death with defects of the glossopharyngeal ganglion and axonal projections [26] and in improper differentiation and premature cell death of cortical subplate neurons [39]. These latter defects lead to failing corticothalamic connectivity. This observation points to a specific role of this factor in a subset of neurons that express it. Similarly, only a subset of neurons expressing the orphan receptor Nurr1 display a phenotype after null mutation [30,36,38]. Nurr1 appears to play an essential role in the phenotype induction and ultimate survival of mesencephalic dopaminergic neurons. These findings suggest that orphan receptors are part of complex, cell-specific cascades that determine differentiation and cell fate. TR4 expression overlaps to a large extend with COUPTFI and ARP-1 at early developmental stages of the CNS, but gains its own expression pattern around birth. The present studies show that the TR4 gene is subject to strict spatiotemporal regulation during development, and undergoes suppression restricting its expression during development. While this study focussed on the developmental regulation of the TR4 gene, we did not aim to distinguish between different splice variants and to detect protein. The cellular function of TR4 protein in developing neural tissue remains to be established in future studies. It may be speculated that it also participates in molecular cascades in a cell-dependent manner for which null mutation will be essential. TR4 has a broad specificity for binding to regulatory regions of genes having direct repeats of the AGGTCA nucleotide motif. These nucleotide motifs are common to many nuclear receptors, including COUP-TFI and ARP-1. COUP-TFI and ARP-1 can interfere with responses to hormones through competitive binding to response elements of RARs and THRs. TR4 displays a marked difference in transcriptional activity dependent on the configuration of the response element. It can either act as a repressor on direct repeats spaced by 1 or 2 nucleotides (DR1, DR2) [14,35] as well as an activator on DR4 [15] and act through single motifs (unpublished results).

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Thus, it can interfere with the RAR / RXR signalling pathways and exert negative regulation on response elements [8,14], but also enhance the effects of thyroid hormone [15]. Moreover, interactions of TR4 with different co-regulators dependent on the response element it binds to [16] and with other nuclear receptors, e.g. the androgen receptor [17] even expands its regulatory potential in a cell-type dependent manner. Therefore, TR4 may have distinct functions in the cellular networks composed of complex sets of nuclear hormone receptors that govern brain development. Further characterization of response elements, its mode of gene activation and the identification of potential neuronal target genes in specific neuronal subsets will be of interest to define its function in the CNS.

Acknowledgements We are grateful to J.J. Cox-Van Put for excellent technical assistance. This research was supported by The Netherlands Organization for Scientific Research NWOMW (900-546-109).

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