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(The FASEB Journal. 2000;14:2171-2176.)
© 2000 FASEB

Subcellular localization of presenilins during mouse preimplantation development

SUNG-JIN JEONG*,{dagger}, HYE-SUN KIM*, KEUN-A CHANG*, DONG-HO GEUM{dagger}, CHEOL HYOUNG PARK*, JI-HEUI SEO*, JONG-CHEOL RAH*, JUN HO LEE*, SE HOON CHOI*, SANG GOO LEE{dagger}, KYUNGJIN KIM{dagger} and YOO-HUN SUH*1

* Department of Pharmacology, College of Medicine and Neuroscience Research Institute, Medical Research Center, Seoul National University, and Biomedical Brain Research Center, Korea National Institute of Health, 110–799 Seoul, South Korea; and
{dagger} Department of Molecular Biology and Cell Differentiation Research Center, College of Natural Sciences, Seoul National University, 151–742 Seoul, South Korea

1Correspondence: Department of Pharmacology, College of Medicine, Seoul National University, 28 Yongon-Dong, Chongno-Gu, Seoul 110–799. E-mail: yhsuh{at}plaza.snu.ac.kr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The genes defective in familial Alzheimer’s disease encode the proteins presenilin 1 and 2 (PS1 and 2). Expression of presenilins (PSs) and their proteolytic processing are regulated during neuronal development. Even though these proteins are detected and regulated mainly in Golgi and endoplasmic reticulum, their subcellular distribution during the development is not known. The present study aimed to investigate the localization of PSs and their role during early developmental stage using mouse embryo model. At preimplantation stage, PSs were detected not only in cytoplasm, but also in the nucleus from oocyte to 2.5 dpc (day postcoitum), then disappeared in the nucleus at blastocyst stage (3.5 dpc). Antisense against PS1 and PS2 decreased the transition to blastocyst stage, whereas each antisense alone had no effect. Treatment with lactacystin (26S proteosome inhibitor), which arrest cell cycle at M phase, redistributed PSs into centrosome-kinetochore microtubule. PS2 overexpression in HEK 293 cell arrested cell cycle at S phase. These data suggest that PSs play key roles in cell division and differentiation during early development.—Jeong, S.-J., Kim, H.-S., Chang, K.-A., Geum, D.-H., Park, C. H., Seo, J.-H., Rah, J.-C., Lee, J. H., Choi, S. H., Lee, S. G., Kim, K., Suh, Y.-H. Subcellular localization of presenilins during mouse preimplantation development.


Key Words: preimplantation embryos • nucleus • centrosome-kinetochore microtubule • cell division


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ALZHEIMER’S DISEASE is the most common neurodegenerative disorder presenting progressive dementia. Presenilin 1 and 2 (PSs), which have been identified to be located on chromosomes 14 and 1, are responsible for most familial Alzheimer’s disease (FAD) (1 2 3) . Several mutations in PSs lead to increased production of Aß42, which might be critical for the pathogenesis of FAD (4 , 5) . However, the normal function of PSs is not well known.

Recent reports suggest that PSs are regulated during neural development (6) . PS1 knockout mice showed developmental abnormalities including the somite malformation and cerebral hemorrhage (7) . Amyloid precursor protein (APP), Notch, or ß-catenin, which are associated with PSs (8 , 9) , are also expressed from early development (10 11 12) , suggesting that the association between PSs and the related proteins may play a critical role in the developmental process.

PSs are known to be localized in endoplasmic reticulum (ER) and Golgi apparatus (13 , 14) . In human fibroblasts and lymphoblastoid cells, PSs are also detected in centrosome, suggesting PSs may regulate the cell division (15) . However, their subcellular localization and function during cell division are not well known.

The mouse embryo could basically offer an invaluable model system to examine the functional roles of PSs in cell division and development. As a step toward understanding the roles of PSs, the present study attempted to examine the intracellular localization and the roles of PSs in cell division using early embryos.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Antibodies
Two different antibodies were used for immunodetection of PS1; {alpha}PS1 Loop, a rabbit polyclonal antibody generated against amino acid 263–407 of the Loop region of PS1 (a kind gift from Dr. G. Thinakaran and S. Sisodia) (16) , and S182 NT(PS1NT), an affinity-purified goat polyclonal antibody against amino-terminal region of PS1 (Santa Cruz, Santa Cruz, Calif.). For PS2, STM2 CT (PS2CT), a goat polyclonal antibody against carboxyl-terminal region of PS2 (Santa Cruz), was used. Tubulin-ß 65 ß-3 for microtubule (monoclonal, NeoMarkers, Calif.) and 22C11 for APP (monoclonal, Boehringer Mannheim, Mannheim, Germany) were used.

Collection of oocyte and preimplantation embryos
The care and treatment of the mice used in these experiments were in accordance with Seoul National University institutional guidelines. To collect oocytes, 3-wk-old ICR female mice were killed by cervical dislocation and ovaries were dissected. To release oocytes, the dissected ovaries were placed on 35 mm culture dish in M16 medium and punctured under the dissecting microscope. Fully grown oocytes with intact germinal vesicle were then collected and washed several times with fresh medium before immunocytochemistry.

To obtain preimplantation mouse embryos, adult female mice (5–7 wk old) were superovulated by injecting 5 IU of human chorionic gonadotropin after 5 IU of PMSG (pregnant mare serum gonadotropin) administration. They were mated with fertile male mice of the same strain. Embryos were flushed from oviducts or uterine horns at different time points according to their development schedule.

Immunocytochemical analysis
Embryos were washed with PBS (phosphate-buffered saline) containing 3% FBS (fetal bovine serum) and fixed in 4% paraformaldehyde for 10 min at room temperature. They were treated with 50 mM NH4Cl in PBS for 1 h for quenching and then permeabilized for 30 min (20 mM HEPES, 300 mM sucrose, 50 mM NaCl, 3 mM MgCl2, and 0.5% Triton X-100, pH 7.4). After blocking with 3% FBS-PBS for 1 h, PS antibodies were incubated for 2 h at room temperature, and then tubulin-ß antibody for 2 h All antibodies for PSs were used at a dilution of 1:10. For preabsorption controls, synthetic peptides (Santa Cruz) were incubated for 2 h before immunocytochemistry. For secondary antibodies, FITC-conjugated donkey anti-goat IgG (Jackson ImmunoResearch Laboratories, West Grove, Pa.), anti-rabbit IgG (Oncor, Gaithersburg, Md.), and Cy3-anti-mouse IgG (Zymed, San Francisco, Calif.) were used. After incubation with secondary antibodies, embryos were washed and transferred onto the silane-coated microslides (Muto Pure Chemicals Co., Tokyo, Japan). They were mounted with media containing propidium iodide (PI) (Oncor). Confocal microscope was performed using a Bio-Rad MRC 1024. All immunocytochemistry experiments in this study were done with more than 35 embryos.

Culture in the presence of proteasome inhibitors or antisense oligonucleotides
Embryos were incubated in the presence of 10 µM of lactacystin, N-acetyl-leucyl-leucyl-norleucine (ALLN), and MG132 (Calbiochem, San Diego, Calif.) at 37°C. Embryos from 0.5 to 2.5 dpc were incubated overnight and then counted for developmental stage. Embryos at the blastocyst stage were incubated for only 4 h and examined for the PSs localization.

The antisense oligonucleotides used in this study were designed to be complementary to 18 or 24 bases including downstream of the initiation codon of the mouse PS1 or PS2 mRNA (for PS1: 5'-tgcaggtatctctgtcat; for PS2: 5'-gtcagaggccaggaatgcgagcat). For control, sense oligonucleotides having the same region to the antisense oligonucleotides were also used. PS1 or PS2 antisense, or both, were incubated for 24 h at a concentration of 10 µM. Embryos at 2.5 dpc were used and scored for their developmental transition from morula to blastocyst.

Transient transfection and fluorescence-activated cell sorting (FACS) analysis
Human kidney cells (HEK293) were plated on a 35 mm dish (2x105 cells) and transfected with 4 µg wild-type PS2 (PS2WT) or mutant PS2 (PS2N141I) in pcDNA3 using 10 µg of Dosper (Boehringer Mannheim). For FACS analysis, they were trypsinized and resuspended in PBS 24 h after transfection. After centrifugation for 5 min at 200 rpm, fixation in 70% ethanol was performed for 5 min. Cells were permeabilized with 0.1% Triton X-100 on ice for 5 min. Propidium iodide (30 µg/ml) with 300 µg/ml RNase A in PBS was used to stain cells. Cells were counted on a FACS Calibur cell sorter using CelQuest software (Beckton Dickinson, Mountain View, Calif.) and the percentages of cells in the G1, S, and G2/M phases of the cell cycle were determined using ModFit LT software.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Localization of PS1 and PS2 during the mouse preimplantation period
PS1NT and PS2CT immunoreactivities were detected in the nucleus and cytoplasm (Fig. 1A , B ). The same findings were observed when oocytes were stained with {alpha}PS1 Loop antibody (data not shown). However, PSs immunoreactivities were absent in nucleoli (Fig. 1A , B ). No PSs immunoreactivities were observed when the primary antibodies were omitted or the peptides against each antibodies were preabsorbed (Fig. 1A ). At 1.5 dpc (2–4 cell stage) and 2.5 dpc (8 cell, morula stage), PSs were detected in both the cytoplasm and nucleus. However, they disappeared from the nucleus at blastocyst stage (3.5 dpc) (Fig. 2 ). The specificity of the antibodies used for this study was determined by the peptide preabsorption with either PS1 amino-terminal peptide or PS2 carboxyl-terminal peptide (Fig. 2) .



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  		Figure 1. Localization of PSs in the nucleus and cytoplasm in mouse oocyte. A) Oocytes at germinal vesicle (GV) stage were labeled with antibodies against PS1 (PS1NT) and PS2 (PS2CT) and stained with PI for staining the nucleus. PSs were visualized with an FITC-labeled secondary antibody. Control (C) was incubated with only 3% FBS-PBS or preabsorbed with each peptide against PS1NT or PS2CT antibody. Oocytes show nucleus (N; arrowhead), nucleoli (Nc; arrow), and cytoplasm (Cyt; bar). Magnification; x630. B) The histogram converted from panel A shows the relative expression level of PSs in nucleus (N), nucleoli (Nc), and cytoplasm (Cyt) under a confocal microscopy.



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  		Figure 2. Alteration of PSs localization during the preimplantation period. A) Embryos from 1.5 to 3.5 dpc were labeled with PS1NT antibody (PS1NT) or PS2CT antibody (PS2CT) before PI staining. PSs were visualized with an FITC-labeled secondary antibody. Controls were incubated only with 3% FBS-PBS (Control) and negative controls were preabsorbed with amino-terminal peptide of PS1 (NT-PS1NT) or carboxyl-terminal peptide of PS2 (CT-PS2CT). Magnification: x630. B) Higher magnification shows the presence of PS2 (white box in panel A) in nucleus (N; arrowhead), cytoplasm (Cyt; bar), and nucleoli (Nc; arrow) at 2.5 dpc and 3.5 dpc.

Localization of PSs in the microtubule by the treatment of embryo with lactacystin
After the lactacystin treatment, one-cell embryos at 0.5 dpc were completely transited to two-cell stage over 90%. However, less than 7% of the embryos at 1.5 dpc and 2.5 dpc developed to the next stage (data not shown). Since all the 3.5 dpc embryos died after overnight incubation with lactacystin, they were treated only for 4 h. Some embryos treated with 26S proteasome inhibitors were arrested mainly at M phase, where chromatids, kinetochore, and centrosome-kinetochore microtubules are observed.

Immunoreactive PSs reappeared in the nucleus after lactacystin (Fig. 3A , B , C ), ALLN, and MG132 treatment (data not shown). Treatment of proteasome inhibitors also increased the intensities of PSs immunoreactives (Fig. 3C ). Unlike the PSs, APP was not detected in the nucleus of embryos (3.5 dpc) when treated with lactacystin (Fig. 3A , B ). Ubiquitin was expressed in both cytoplasm and nucleus at this stage, although the expression level was different (data not shown). In addition, PSs were found in centrosome-kinetochore microtubule at M phase (Fig. 3A , D ), but APP was not localized on the microtubule (Fig. 3A , D ). PSs were intensively stained with tubulin-ß on the centrosome-kinetochore microtubules in blastocyst (Fig. 4A ), but APP was not colocalized with tubulin-ß (data not shown). The colocalization of PSs and tubulin-ß to the microtubule was also observed after treatment with other proteasome inhibitors such as ALLN and MG132 (Fig. 4B ).



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  		Figure 3. Localization of PSs when treated with lactacystin. A) Embryos at 3.5 dpc were treated with 10 µM of lactacystin and stained with the indicated antibodies (PS1NT, PS2CT, or APP). Control (C) was incubated with the preabsorbed antibodies. The nucleus and chromatids were stained with PI. The localization of PSs (white box) and M phase arrested areas (yellow box) are shown at the higher magnification in panels B and D. Nucleus, arrowhead; nucleoli, arrow. C) The histogram shows relative expression level of PSs in nucleoli (Nc), nucleus (N), and cytoplasm (Cyt) after the treatment with lactacystin (+Lactacystin) or not (-Lactacystin).



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  		Figure 4. Colocalization of PSs and tubulin-ß in the centrosome-kinetochore microtubules after treatment with 26S proteasome inhibitors. A) Embryos (3.5 dpc) treated with lactacystin were immunostained with tubulin-ß and PS1NT or PS2CT. PSs were visualized with an FITC-labeled secondary antibody and tubulin-ß was visualized with an Cy3-labeled secondary antibody. The colocalization of PSs and tubulin-ß at cell cycle-arrested areas are shown as yellow color (arrow). B) Embryos (3.5 dpc) treated with ALLN or MG132 were immunostained with PS2CT and tubulin-ß at M phase (yellow color; arrow). Magnification: x630

Effect of antisense oligonucleotides against PSs on the cell division and differentiation
Neither PS1 nor PS2 antisense alone affected development (Fig. 5A ). However, incubation with both antisenses significantly inhibited the cell division and induced the abnormal morphology (Fig. 5B ). The transition to the next stage was also inhibited more than 80.1% when treated with both antisense oligonucleotides (Fig. 5A ). The embryos treated with sense oligonucleotides normally developed to blastocyst, showing inner cell mass, trophectoderm, and blastocoele (86.1%; control 86.7%) (Fig. 5A , B ).



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  		Figure 5. Inhibitory effect of antisense oligonucleotides against PSs on the cell division and differentiation. A) Embryos at 2.5 dpc were cultured in vehicle only (Control), sense oligonucleotide (Sense), either PS1 (PS1Anti) or PS2 (PS2Anti) antisense oligonucleotide, or both PS1 and 2 antisense (Antisense) at 10 µM for 24 h. The embryos transited to blastocyst were counted. *P < 0.01 by Student’s t test. B) Embryos cultured in the presence of either sense oligonucleotides (Sense) or both antisenses (Antisense) were observed under phase contrast microscope. Blastocyst shows inner cell mass (ICM), trophectoderm (TF), and blastocoele (BC) when treated with PS1 or PS2 antisense alone or sense oligonucleotide (Sense). Magnification: x100

Effect of PS2 overexpression on the cell cycle of HEK293 cells
DNA content was measured by FACS analysis in HEK293 cells transfected with mock, PS2 wild type (PS2WT), and PS2 mutant (PS2N141I). Cells overexpressing wild or mutant PS2 were accumulated at S phase (Fig. 6 ). Apoptosis increased in the cells with PS2 overexpression (data not shown).



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  		Figure 6. Effect of presenilin 2 overexpression on cell cycle. Exponentially growing HEK293 cells were transfected with mock (Mock), PS2WT and PS2N141I and stained with propidium iodide. DNA content was measured by FACS analysis (data representative of three experiments).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We demonstrated that PSs were expressed throughout early development. It was reported that PSs are ubiquitously expressed during the neural development of several species including mouse, rat, Drosophila, and Xenopus. (6 , 12 , 17 , 18) , suggesting presenilin may be one of the proteins that control neural development. Our findings showed that presenilins also play a role in the cell division early in the development before nervous system development.

PSs are known to be localized mainly in the Golgi complex and ER of several neuronal cells (13 , 14) . We showed altered PSs localization during the early developmental stages. They are distributed in the nucleus, but not in nucleoli. Absence in the nucleoli does not indicate that PSs may be involved in the functions of nucleoli such as ribosome assembly, transcriptional regulation, or nuclear export of certain mRNA including c-myc and telomerase (19) . The functional significance of intranuclear localization of PSs is not known. However, the presence of several putative DNA binding motifs in PS1 may explain the existence of PSs in the nucleus (20) . After the processing through Golgi complex and ER, PS1 may be translocated into the nucleus via nuclear membrane using their nucleus localization signal. In this study, we could not clarify whether nuclear PS1 forms are full length or fragment.

In the experiment with Drosophila development, presenilin (PSn) was expressed mainly in the nurse and follicle cells throughout the oogenesis, but not in oocytes. The initiation of PSn expression was from the blastoderm stage, mainly in the cytoplasmic distribution (12) . It could not be determined whether there are some differences in the expression and localization of the specific genes between species.

Our results suggest the possibility that nuclear PSs are degraded by 26S proteasome complex during developmental stage. The proteins regulating cell cycle are known to be degraded by the ubiquitin system at the appropriate times during the cell division. The proteasome complex is intensively localized in the nucleus as well as cytoplasm in the rat CNS (21) . 26S proteasome is the major nonlysosomal protease that degrades or processes the short-lived proteins by ATP/ubiquitin dependent proteolysis and is involved in the basic cellular process (22 , 23 , 24) . It was reported that the full length of PS1 is degraded by 26S proteasome and cleaved at the putative processing site after Met288 and Glu299 by the proteasome pathway (25 26 27) .

We demonstrated that PSs were localized on the centrosome-kinetochore microtubules. Centrosome, kinetochore, and microtubules between centrosome and kinetochore are essential mitotic apparatus for cell division. Li et al. (15) reported that the PSs were localized in centrosome at interphase of the human fibroblast and COS cell. Our results suggest that the PSs may play a role as a kinetochore receptor in assembly of the microtubule during mitosis.

It has been also reported that many PSs’ partners are cytoskeletal proteins. The Loop region of PSs interacts with the nonmuscle filamen (actin binding protein 280, ABP280) and Fh1 (filamin homologue 1), a structurally related protein that is detected in NTF and dystrophic neurites (28) . PSs are also known to be directly associated with tau, a microtubule-associated protein (29) . We showed that PSs were colocalized with tubulin-ß, a component involved in the organization of the microtubules (MTs) with tubulin-{alpha} (30 , 31) . The alteration in association of PSs and tubulin-ß may play a key role during mitosis as well as cytoskeletal roles in determining the morphology and cell division during development.

We demonstrated the inhibitory effects of PS1 and 2 antisense on cell division and differentiation. However, either PS1 or PS2 antisense alone had no effect on the cell division. Antisense oligonucleotides have generated wide interest because of their potential to inhibit expression of specific genes in cells. Many studies have shown the roles of the important genes in the early development using antisense oligonucleotides (32 , 33) . Our results suggest that both PS1 and 2 might be required coordinately for the cell division during the preimplantation development. The effects of PSs on cell division and differentiation remain to be tested in the future using the double PSs knockout mouse.

In our study, the overexpression of wild or mutant PS2 arrested the cell cycle at S phase and increased apoptotic feature. The overexpression study with ß-catenin, one of presenilin’s partners, increased the proportion of S and G2 phase in MDCK cell line (a canine kidney-derived nontransformed epithelial cell line) (34) . Recently, it was reported that HeLa cells was arrested at G1 phase when they are transfected by PS2 (35) . Therefore, alteration of cell cycle machinery in nonprogenitor neuronal populations seems to be associated with deleterious consequences, and abortive progression through the cell cycle has been shown to be related to cellular dysfunction and often cell death, i.e., all of the seminal pathological features of AD (36) .

Taken together, the absence or overexpression of PSs may induce inappropriate arrest of cell cycle and lead to cell death.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge Drs. Tae-Wan Kim, Jean-Pyo Lee, and Man Ho Kim for useful comments as well as Jun-Seok Huh, Cheol-Jun Seok, and Hyang-Min Jeong for technical assistance. We are especially grateful to Drs. Sangram Sisodia, Thinakaran Gopal, and Seong-Hun Kim for the {alpha}PS1 Loop antibody. This work was supported in part by a grant from the Ministry of Health and Welfare and Seoul National University Hospital.

Received for publication December 30, 1999. Revision received April 24, 2000.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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