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Volume 17, Number 9, Issue of May 1, 1997 pp. 3014-3023
Copyright ©1997 Society for NeuroscienceThe mGluR6 5
Upstream Transgene Sequence Directs a Cell-Specific and Developmentally Regulated Expression in Retinal Rod and ON-Type Cone Bipolar Cells
Yoshiki Ueda1, Hideki Iwakabe1, Masayuki Masu1, Misao Suzuki2, and Shigetada Nakanishi1 1 Department of Biological Sciences, Kyoto University Faculty of Medicine, Kyoto 606-01, Japan, and 2 Institute of Molecular Embryology and Genetics, Kumamoto University Medical School, Kumamoto 862, Japan
ABSTRACT
We generated transgenic mice, using 9.5 kilobase pairs of the 5
Key words: transgenic mouse; metabotropic glutamate receptor;upstream sequence from the mouse metabotropic glutamate receptor subtype 6 (mGluR6) gene fused to the
-galactosidase (lacZ) reporter gene, and investigated the promoter function of the cell-specific and developmentally regulated expression of mGluR6. Most of the independent transgenic lines commonly showed the lacZ expression in the defined cell layers of the retina, and four transgenic lines were characterized in detail for cell-specific lacZ expression patterns by X-gal staining and lacZ immunostaining. The lacZ-expressing retinal cells were classified into two cell types. One cell type was identified as rod bipolar cells on the basis of colocalization of protein kinase C (PKC) immunoreactivity and morphological criteria. The other cell type was PKC-immunonegative and resided at the cell layers corresponding precisely to ON-type cone bipolar cells. The latter bipolar cells were found to exist as a large cell population comparable to rod bipolar cells. This observation was confirmed by coimmunostaining of dissociated retinal cells with the lacZ and PKC antibodies. The ontogeny analysis indicated that the lacZ expression completely agrees with a temporal expression pattern of mGluR6 during retinal development. This study demonstrates that the mGluR6 5
INTRODUCTION
Visual information is segregated into parallel ON and OFF pathways at retinal bipolar cells (Miller and Slaughter, 1986
; Dowling, 1987
Electrophysiological evidence indicated that ON-type bipolar cells have a specific metabotropic glutamate receptor (mGluR) that activates cGMP phosphodiesterase via a G-protein (Nawy and Jahr, 1990
The characteristic expression pattern of mGluR6 in retinal bipolar cells raises an interesting question regarding the regulatory sequence and mechanism that determine a cell type-specific and developmentally regulated expression of the mGluR6 gene. In addition, although the role of mGluR6 in postsynaptic transmission to rod bipolar cells had been well established (Shiells, 1994
MATERIALS AND METHODS
Plasmid construction. We cloned and mapped the mouse genomic DNAs containing the mGluR6 gene from a mouse genomic library prepared from 129/SvJ mice DNA (Stratagene, La Jolla, CA) by hybridization with the 665 base pair (bp) DraII fragment of the rat mGluR6 cDNA (Nakajima et al., 1993
Fig. 1. The MG6-Z transgene structure, the mouse mGluR6 genomic sequence around the potential transcription initiation site, and Northern blot analyses of transgenic mice. A, The MG6-Z transgene used for generation of transgenic mice was constructed from three different DNA fragments according to the procedures described under Materials and Methods. The restriction sites shown by arrows indicate the fusion sites; Sp, SphI; N, NaeI; H, HindIII; P, PstI; B, BamHI. The SphI-NaeI fragment represents the mGluR6 upstream sequence. The HindIII-PstI fragment contains the gpt, trpS, lacZ, and SV40 sequences. The PstI-BamHI fragment encodes the SV40 sequence. The region around the translation initiation site of the transgene is expanded below the MG6-Z transgene; the shaded region indicates the gpt and trpS structures. The numbers shown below stand for nucleotide positions of the 5
[View Larger Version of this Image (50K GIF file)]
Generation of transgenic animals. The MG6-Z gene was extracted from the recombinant plasmid by digestion with SalI and SacII; the SalI-SacII fragment was fractionated by electrophoresis on a 0.5% low-melting-point agarose and purified by silica matrix (Glassmilk, Bio 101, La Jolla, CA). The DNA fragment (30 µg/ml) eluted in 1 mM Tris-Cl and 0.1 mM EDTA, pH 8.0, was microinjected into pronuclei of BDF1 (C57BL/6J × DBA/2J) fertilized one-cell embryos. Injected embryos were transplanted into the oviducts of pseudopregnant female mice. One hundred and twenty-four founder mice were produced. Integration of the lacZ gene was analyzed by Southern blot hybridization of BamHI-digested tail DNAs with a radiolabeled ClaI-SacI fragment of the lacZ gene. Thirteen of 24 transgenic lines that were lacZ gene-positive passed their transgenes onto their offspring. Total RNA was extracted by the acid guanidinium-phenol-chloroform method (Isogen, Nippon Gene, Tokyo, Japan), and poly(A+) RNA was purified by oligo(dT)30-conjugated latex particles (Oligotex dT30, Takara, Ohtsu, Japan). Northern blot analysis was performed by blot hybridization of 2 µg poly(A+) RNA with the above lacZ probe.
Antibodies. The primary antibodies were purchased as follows: mouse monoclonal antibodies against protein kinase C (PKC) (MC5) from Amersham (Buckinghamshire, UK) and against lacZ from Boehringer Mannheim (Mannheim, Germany), and rabbit polyclonal antibodies against PKC -isoform from Boehringer Mannheim and against lacZ from Cappel (Durham, NC); these antibodies were diluted at 1:100 for use. Mouse monoclonal antibody against PKC was reported to be reactive with only PKC
Histochemistry and immunostaining. The animals used were heterozygous transgenic mice 1-4 months old, unless otherwise stated. After anesthesia with diethylether, an animal was perfused via the left ventricle with 0.01 M PBS, pH 7.3, followed by fixatives in PBS. Glutaraldehyde (0.4%) was used for X-gal staining, and 4% formaldehyde was used for fluorescence immunostaining. Perfusion was omitted for very young pups, which were decapitated immediately after anesthesia. Eyes were enucleated and immersed in the same fixative solution for 10 min. When lacZ immunoreactivity was examined, eyes were dissected at the limbus, and retinas were isolated mechanically and immersed in the fixative solution for another 2 hr. After fixation, whole eyes or isolated retinas were cryoprotected with 10% sucrose and then 15% sucrose for 10 min, embedded in O.C.T. compound (Miles, Elkhart, IN), and frozen in liquid nitrogen. The samples were sectioned at 10 µm on a cryostat at 17°C. Mounted sections were air-dried for 10-30 min and rinsed in PBS. X-gal staining was performed for 4-8 hr in a staining solution [1 mg/ml X-gal, 17.5 mM K3Fe(CN)6, 17.5 mM K4Fe(CN)6, 1 mM MgCl2, and 0.2% Nonidet-40 in PBS] at 37°C. For some samples counterstaining was performed with neutral red. For X-gal staining of the brain, mice were perfused and fixed with 0.4% glutaraldehyde in PBS. Whole brains were removed and immersed in the same fixative solution for another 30 min. Then the brain was incubated with the X-gal reaction solution for 6-8 hr at 37°C. In most cases X-gal staining was observed externally, but in some cases with no such external staining, brains were cryoprotected as described above and embedded in O.C.T. compound. The frozen samples then were sectioned at 40-50 µm thicknesses with a cryostat and mounted on slide glasses.
For immunofluorescence staining, mounted sections were rinsed, preincubated with 2% normal goat serum in PBS, and incubated overnight with the primary antibody at 4°C. The sections were reacted with the secondary biotinylated antibody at room temperature for 1 hr and then with the fluorochrome-conjugated secondary antibody and fluorochrome-avidin complex at room temperature for 30 min. After final rinsing with PBS, the samples were coverslipped with a glycerol/PBS (1:1) solution containing 0.1% p-phenylenediamine (Sigma, St. Louis, MO), and the edge of the coverslip was sealed with nail enamel. Fluorescence immunoreactivity was viewed by confocal microscopy. For quantitative analysis of differently immunoreactive cells, the cell number was counted in a confocal image dissected at 1.2 µm thicknesses.
Cell dissociation and immunostaining. Dissociated bipolar cells were prepared according to the procedures described previously (Ueda et al., 1992
RESULTS
Generation of the mGluR6/lacZ transgenic mice
To address whether the mGluR6 upstream sequence is capable of directing its expression in a cell-specific and developmentally regulated manner, we fused the 5
The fusion gene was microinjected into fertilized mouse eggs, which then were transferred to foster mothers. On blot hybridization analysis of tail DNAs, we identified 13 independent transgenic lines that passed their transgenes onto their offspring. All but three lines exhibited an X-gal-positive staining in the defined cell layers of the retina. However, because some of these transgenic mice also showed an X-gal staining in particular brain regions, depending on individual transgenic lines, we chose and characterized in more detail three male lines (ZM23, ZM39, and ZM41), in which lacZ was expressed restrictedly in the retina, and one female line (ZF35), in which lacZ was detected in the retina and a part of the amygdala. Blot hybridization analysis of tail DNAs indicated that ZF35, ZM23, ZM39, and ZM41 possessed ~7-8, ~5-6, ~1-2, and ~40-50 copies of the lacZ gene in the genomic DNA, respectively (data not shown). The tissue specificity of the lacZ expression was analyzed by Northern blot hybridization of poly(A+) RNA of the retina, cerebral cortex, cerebellum, and brainstem isolated from these four transgenic animals (Fig. 1C). This analysis revealed that in the ZF35, ZM23, and ZM39 lines two species of lacZ mRNA, which probably were generated by different polyadenylations, were expressed selectively in the retina and in no other parts of the brain. The amount of the LacZ mRNA expressed approximately paralleled the number of the integrated lacZ genes in these transgenic lines. However, no appreciable lacZ mRNA was detected in any parts of poly (A+) RNA in the ZM41 line despite an insertion of multiple copies of the lacZ gene in this transgenic mouse. LacZ expression pattern in retinal bipolar cells
We first examined an X-gal staining pattern in transverse retinal sections of the four transgenic lines (Fig. 2). The densities of the X-gal reaction product were not identical among the four transgenic mice. ZF35 and ZM23 showed a strong and dense staining, whereas ZM39 was weak in X-gal staining. ZM41 exhibited a sparse and compartmentalized staining throughout the retinal section. The densities of the X-gal staining corresponded to expression levels of the lacZ mRNA in the transgenic lines. The retina consists of several different cell layers: the outer nuclear layer (ONL), composed of photoreceptors; the inner nuclear layer (INL), consisting of bipolar, horizontal, and amacrine cells; and the ganglion cell layer (GCL), containing mostly ganglion cells. Photoreceptors, bipolar cells, and horizontal cells make synaptic connections in the outer plexiform layer (OPL), whereas bipolar, amacrine, and ganglion cells make contact in the inner plexiform layer (IPL). The ON-type and OFF-type bipolar cells seem to differ in stratification levels of their axon terminals in the IPL and probably are correlated to an inner (sublamina b) and outer (sublamina a) stratification of their axon terminals, respectively (Wässle and Boycott, 1991
Fig. 2. X-gal staining of transverse retinal sections of the four transgenic mice. The densities of the X-gal reaction product are different among the four transgenic lines, but the X-gal staining is commonly observed in the cell bodies at the outer portion of the INL and in the axon terminals at the inner portion of the IPL. a, Sublamina a; b, sublamina b. Scale bars in this figure and the subsequent figures, except for Figure 7, represent 10 µm.
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We also performed immunostaining of transverse sections of retina with anti-lacZ antibody and examined an immunostaining pattern of lacZ expression via confocal microscopy. The immunofluorescent patterns of the lacZ expression were identical with the X-gal staining patterns in all four transgenic mice (Fig. 3A-D). In these sections mGluR6 immunoreactivity also was examined by coimmunostaining with the mGluR6-specific antibody, and punctate mGluR6 immunoreactivity, like the wild-type mouse retina (Masu et al., 1995 
Fig. 3. Double-immunofluorescence staining of lacZ and mGluR6 immunoreactivities in transverse retinal sections of the four transgenic mice. The densities and patterns of lacZ immunoreactivity (A-D) are identical to those of the X-gal staining indicated in Figure 2. Punctate mGluR6 immunoreactivity (E-H) is seen only at the OPL and is not affected by different expression levels of lacZ in the four transgenic lines.
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Cell types expressing lacZ in the retina
Rod bipolar cells have been shown to be labeled selectively with the antibody against PKC (Negishi et al., 1988
Fig. 4. Double-immunofluorescence staining of lacZ and PKC immunoreactivities in transverse retinal sections of the four transgenic mice. Double-immunofluorescence staining of the lacZ and PKC immunoreactivities was performed by two different combinations of primary antibodies against PKC (red) and lacZ (green): polyclonal anti-lacZ rabbit IgG and monoclonal anti-PKC mouse IgG (A, C, E-G) and monoclonal anti-lacZ mouse IgG and polyclonal anti-PKC rabbit IgG (B, D). More magnified views showing immunoreactive cell bodies are indicated in C and D. Two types of cell bodies showing lacZ-positive/PKC-positive immunoreactivity (yellow) and lacZ-positive/PKC-negative immunoreactivity (green) are seen clearly in retinal sections of all four transgenic mice. The axon terminals of lacZ-positive/PKC-positive rod bipolar cells reside in the innermost part of the IPL close to the GCL, whereas those of lacZ-positive/PKC-negative bipolar cells reside in the outer half of sublamina b (b) of the IPL. LacZ-negative/PKC-positive amacrine cells also are seen, as indicated by arrows. Immunoreactivity seen at the GCL in all preparations is noted as a nonspecific immunoreaction with rabbit IgG, because this immunoreactivity is seen as dependent on the use of rabbit IgG but independent of immunostaining with either lacZ or PKC.
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Remarkably, a large number of PKC-negative but lacZ-positive cells were detected in all four transgenic lines. Their cell bodies were located at the position similar or close to the rod bipolar cell bodies in the outer part of the INL, and their axon terminals resided in the outer half of sublamina b of the IPL (Fig. 4). This characteristic spatial pattern of both lacZ-positive/PKC-positive and lacZ-positive/PKC-negative cells was commonly observed in the four transgenic lines, although expression levels of lacZ were different among them (Fig. 4A,E-G). Recently, Euler et al. (1996)
On the basis of the above finding, we estimated the cell number of different immunoreactive cells from transverse retinal sections of the adult ZF35 transgenic mice (2-4 months). Cells were counted from 19 confocal images without taking into consideration the locations of retinal sections. The sums of the counted cells were as follows: lacZ-positive cells, 686; PKC-positive bipolar cells, 311; PKC-positive amacrine cells, 51. The numbers of lacZ-positive/PKC-positive bipolar cells, the lacZ-positive/PKC-negative bipolar cells, and the PKC-positive amacrine cells were 311, 375, and 51, corresponding to relative ratios of 1.0:1.21:0.16. This finding indicates that ON-type cone bipolar cells exist as a large population comparable to rod bipolar cells. Double-immunofluorescence staining in dissociated bipolar cells
To characterize cell types expressing lacZ further, we performed double immunostaining of dissociated bipolar cells. The retina of the ZF35 mouse was dissociated by enzymatic digestion, and dissociated cells were double-immunostained with the lacZ and PKC antibodies. In a dissociated cell preparation, there were many lacZ-positive/PKC-positive cells with a typical rod bipolar cell morphology with a long axonal extension (Fig. 5). In addition, a large number of lacZ-positive/PKC-negative cells were observed (Fig. 5). Some of them could not be distinguished as either nonspecifically stained cell debris or enzymatically damaged lacZ-positive/PKC-negative cells (Fig. 5A,B). However, many other lacZ-positive/PKC-negative cells showed a cell shape with a short dendritic or axonal process (arrows in Fig. 5B and Fig. 5C,D). Furthermore, consistent with the double-immunofluorescence staining of a retinal section, lacZ-positive/PKC-negative cells existed in comparable numbers to the lacZ-positive/PKC-positive rod bipolar cells. This finding crucially demonstrates that a subpopulation of lacZ-expressing bipolar cells is PKC-negative.
Fig. 5. Double-immunofluorescence staining of dissociated bipolar cells of the ZF35 transgenic mouse by anti-lacZ and anti-PKC. A, B, There are comparable numbers of lacZ-positive/PKC-positive and lacZ-positive/PKC-negative cells seen in a densely dispersed preparation. Arrows indicate lacZ-positive/PKC-negative cells showing a cell shape with a dendritic or axonal process. C, D, Two cell types showing a more intact morphology are indicated.
[View Larger Version of this Image (45K GIF file)]
We also confirmed coexpression of mGluR6 and lacZ in a single cell by double immunostaining of dissociated bipolar cells with the lacZ and mGluR6 antibodies. As reported previously (Nomura et al., 1994 
Fig. 6. Colocalization of lacZ and mGluR6 immunoreactivities in a single cell. A dissociated bipolar cell derived from the ZF35 mouse on PD15 was double-immunostained with anti-lacZ (A) and anti-mGluR6 (B) antibodies. Intense mGluR6 immunoreactivity is seen on a dendritic tip of a lacZ-positive dissociated bipolar cell.
[View Larger Version of this Image (44K GIF file)]
LacZ expression during retinal development
The expression of mGluR6 initiates and develops during the neonatal period in accordance with an orderly layered retinal cell arrangement and synaptic connections of bipolar cells (Nomura et al., 1994
Fig. 7. X-gal staining in developing retinas. X-gal staining was performed with transverse sections of developing retinas of the ZF35 mice. Retinas were counterstained with neutral red. Both scale bars represent 50 µm. A, The PD5 retina consists of the GCL and undifferentiated ventricular cells (VC) and shows no X-gal staining. B, On PD6, the ventricular cells develop into the ONL and INL, divided by the OPL. An uneven X-gal staining starts in the middle of the INL and an inner part of the IPL. C, D, The PD7 retina shows an X-gal staining, but this staining is restricted to the central part of the retina. E, On PD13, an X-gal staining spreads close to the ora serrata.
[View Larger Version of this Image (84K GIF file)]
The developmental regulation of lacZ expression also was examined by double-immunofluorescence staining with the lacZ and mGluR6 antibodies. On PD5, neither lacZ nor mGluR6 was detected (data not shown). On PD7, both mGluR6 and lacZ immunoreactivities were observed faintly and diffusely at the cell body in the INL (Fig. 8A). In addition, axon terminals were also lacZ-positive. On PD13, both immunoreactivities became more manifested (Fig. 8B), and as reported previously (Nomura et al., 1994 
Fig. 8. Double-immunofluorescence staining of lacZ and mGluR6 immunoreactivities in developing retinas of the ZF35 mice. A, The PD7 retina shows weak and diffuse fluorescence for both mGluR6 and lacZ. B, D, On PD13, both lacZ and mGluR6 immunoreactivities are intensified. mGluR6 immunoreactivity is still observed in the cell bodies but gradually moves to the dendritic sides. C, E, On PD28, lacZ immunoreactivity is unchanged, but mGluR6 immunoreactivity is concentrated at the tips of the dendrites. More magnified views of B and C are shown in D and E, respectively.
[View Larger Version of this Image (85K GIF file)]
DISCUSSION
We have investigated the spatial and temporal expression patterns of the lacZ reporter gene under the regulation of 9.5 kbp of the mouse mGluR6 5
In contrast to a wide distribution of the mRNAs for other mGluR subtypes in various brain regions (Nakanishi, 1994
The role of mGluR6 in synaptic transmission from photoreceptors to rod bipolar cells was established by a number of previous studies. mGluR6 shows an agonist profile consistent with the property reported for the mGluR in ON-type bipolar cells (Nakajima et al., 1993
FOOTNOTES
Received Dec. 20, 1996; revised Feb. 7, 1997; accepted Feb. 11, 1997.
This work was supported in part by research grants from the Ministry of Education, Science and Culture of Japan, the Ministry of Health and Welfare of Japan, the Uehara Memorial Foundation, and the Sankyo Foundation. Y.U. was supported by a fellowship of the Japan Society for Promotion of Science.
Correspondence should be addressed to Dr. Shigetada Nakanishi, Department of Biological Sciences, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-01, Japan.
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