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Mice Lacking Methyl-Cpg Binding Protein 1 Have Deficits in Adult Neurogenesis and Hippocampal Function

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Mice Lacking Methyl-Cpg Binding Protein 1 Have Deficits in Adult Neurogenesis and Hippocampal Function Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function Xinyu Zhao*, Tetsuya Ueba*†, Brian R. Christie‡, Basam Barkho*, Michael J. McConnell§, Kinichi Nakashima*, Edward S. Lein*, Brennan D. Eadie‡, Andrew R. Willhoite*, Alysson R. Muotri*, Robert G. Summers*, Jerold Chun§, Kuo-Fen Lee¶, and Fred H. Gage*ʈ *Laboratory of Genetics and ¶Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; §Department of Pharmacology, University of California, 9500 Gilman Drive, La Jolla, CA 92093; and ‡Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, Canada V6T 1Z4 Communicated by Inder M. Verma, The Salk Institute for Biological Studies, San Diego, CA, April 2, 2003 (received for review March 7, 2003) DNA methylation-mediated epigenetic regulation plays critical roles in vivo function of MBD1 is still unclear. Because MBD1 has no in regulating mammalian gene expression, but its role in normal brain sequence specificity, except for methylated CpG, its in vivo target function is not clear. Methyl-CpG binding protein 1 (MBD1), a member genes are not known. of the methylated DNA-binding protein family, has been shown to Maintaining normal DNA methylation levels is critical during bind methylated gene promoters and facilitate transcriptional repres- mammalian development, as demonstrated by the embryonic Ϫ Ϫ sion in vitro. Here we report the generation and analysis of MBD1؊/؊ lethality of Dnmt1 / mice (17). Mutation of the de novo DNA -mice. MBD1؊/؊ mice had no detectable developmental defects and methyltransferase 1-36 (Dnmt3b) causes immunodeficiency, cen -appeared healthy throughout life. However, we found that MBD1؊/؊ tromeric instability, and facial anomalies (ICF) syndrome in hu neural stem cells exhibited reduced neuronal differentiation and mans, with characteristics of genomic instability (18). Both Dnmt1 increased genomic instability. Furthermore, adult MBD1؊/؊ mice had and MeCP2 are highly expressed in the CNS, including postmitotic decreased neurogenesis, impaired spatial learning, and a significant neurons (19). The function of DNA methylation in the adult CNS reduction in long-term potentiation in the dentate gyrus of the is not clear. DNA methylation may maintain a subtle balance of hippocampus. Our findings indicate that DNA methylation is impor- global gene expression pattern, which is crucial for neuronal function (20, 21). Previous work has demonstrated that DNA tant in maintaining cellular genomic stability and is crucial for normal methylation can maintain genomic stability of cells (22). Cells neural stem cell and brain functions. lacking the Dnmt1 gene have 50–100 times higher levels of intra- cisternal A particle (IAP), a type of endogenous virus whose NA methylation at CpG dinucleotides is crucial for silencing expression levels are frequently elevated in cancer cells with Dinactive X-chromosomes, imprinted genes, and parasitic DNA genomic instability (22). However, further studies on other DNA (1). DNA methylation regulates gene expression through two methylation-related proteins are needed to link DNA methylation, mechanisms: (i) methylation at CpG sites blocks the binding of genomic stability and CNS functions. transcription factors and leads to transcriptional inactivation; and To understand the function of DNA methylation and MBD proteins in the mammalian CNS, we generated MBD1-deficient (ii) methyl-CpGs are bound by a family of methyl-CpG binding Ϫ Ϫ proteins (MBDs), including MBD1, MBD2, MBD3, MBD4, and (MBD1 / ) mice. The animals developed normally and appeared MeCP2. Binding of MBDs and further recruitment of histone healthy as adults. We found that MBD1 was expressed in neurons deacetylase (HDAC) repressor complexes result in histone deacety- throughout the brain, with the highest concentration in the hip- lation and inactive chromatin structures that are repressive for pocampus, one of the two regions that have persistent structural transcription (1). The most extensively studied member of this plasticity throughout life in mammals (23). MBD1 was expressed at family is MeCP2, whose mutation causes neurological deficits in a moderate level in dentate gyrus (DG) neurons and at higher levels both humans (Rett Syndrome; ref. 2) and rodents (3–5). Mice in certain immature cells in the subgranular layer (SGL) of the DG. Ϫ/Ϫ This finding led us to investigate the neurogenesis of adult lacking MBD2 show mild maternal behavior deficits (6). MBD3 Ϫ Ϫ Ϫ Ϫ MBD1 / mice. We found that cultured MBD1 / adult neural mice die at an early embryonic stage (6). Mice deficient in MBD4, stem cells (ANCs) had reduced neurogenesis and increased a mismatch repair enzyme, show deficits in DNA repair and genomic instability, and MBD1Ϫ/Ϫ mice had reduced neurogenesis, increased tumor formation (7). impaired spatial learning ability, and marked reduction in DG- MBD1 shares homology with other MBDs only in the methyl- specific long-term potentiation (LTP). Our work demonstrates that NEUROSCIENCE CpG binding domain. Extensive in vitro studies have shown that an MBD protein is important for maintaining genomic stability. MBD1 binds specifically to methylated gene promoters through its The neurological defects in MBD1Ϫ/Ϫ mice are clear examples of MBD domain and carries out transcriptional repression that re- the importance of epigenetic regulation in CNS function. quires its transrepression domain (8, 9). This process requires an unknown HDAC that is different from the HDAC1 mediating the Methods MeCP2 functions (10). MBD1 has functionally unclear zinc finger Gene Targeting Strategy. See Supporting Materials and Methods, motifs (CXXC1, CXXC2, and CXXC3) that share homology with which is published as supporting information on the PNAS web site, DNA methyltransferase-1 (Dnmt1) (11), human trithorax protein www.pnas.org. (12, 13), and human-CpG binding protein (14). The splice variants of MBD1 differ in the number of zinc fingers and in their N- terminal and C-terminal sequences (15). The functional relevance Abbreviations: Dnmt, DNA methyltransferase; MDB, methyl-CpG binding protein; ANC, adult neural stem cell; HDAC, histone deacetylase; IAP, intracisternal A particle; DG, of these splice variants is unknown. In the mammalian genome, dentate gyrus; LTP, long-term potentiation; SKY, spectral karyotyping; X-Gal, 5-bromo-4- MBD1 is concentrated at the heterochromatin sites in centromeric chloro-3-indolyl ␤-D-galactoside. regions, where DNA is highly methylated (10). A single MBD1 gene †Present address: Department of Neurosurgery, Kyoto University Medical School, Kawa- is located on chromosome 18 of both the human and mouse genome harachou Shougoin, Sakyoku, Kyoto 606, Japan. (16). MBD1 is expressed in many tissues, including brain (9, 10). ʈTo whom correspondence should be addressed at: The Salk Institute for Biological Studies, Despite the intense studies performed by using in vitro assays, the Laboratory of Genetics, P.O. Box 85800, San Diego, CA 92186-5800. E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.1131928100 PNAS ͉ May 27, 2003 ͉ vol. 100 ͉ no. 11 ͉ 6777–6782 Animals and Tissues. All mice used were under the 129S4 genetic background, between 2 and 5 months old, and age- and sex-matched between genotypes in each study. All animal procedures were performed according to protocols approved by The Salk Institute for Biological Studies Animal Care and Use Committee. For histology, mice were anesthetized and brains were processed as described (24). For RNA, PCR, and microarray analysis, fresh brains or hippocampi were dissected and frozen immediately on dry ice. In Situ Hybridization, Histology, and Immunohistochemistry. PCR product of MBD1 (411 bp, containing CXXC3) was cloned and used as a template for 35S-labeled riboprobe. In situ hybridization was carried out as described (25). X-Gal (5-bromo-4-chloro-3- indolyl ␤-D-galactoside)stainingwasperformedfor2hat37°C. Floating brain slices (40 ␮M) were used for X-Gal staining and Nissl staining, and images were collected as described (26). Double labeling was analyzed by using a Bio-Rad radiance confocal imaging system. Cell Culture and in Vitro Differentiation Analysis. See Supporting Materials and Methods, which is published as supporting informa- tion on the PNAS web site. Expression Profiling and Real-Time Quantitative PCR. See Supporting Materials and Methods. Western Blotting. The rabbit anti-p73 IAP (gag protein) antibody (1:3,000) used in Western blot was kindly provided by Kira K. Lueders (Laboratory of Biochemistry, National Cancer Institute, Bethesda). The rabbit anti-MBD1 antibody (M254; Santa Cruz Biotechnology) was used at a ratio of 1:1,000. Quantification of IAP Western blotting was done by using NIH IMAGE software with normalization to ␤-actin level. Fig. 1. Histological analysis of the brains of MBD1Ϫ/Ϫ mice. (a) In situ hybrid- ␤ Bisulfite Sequencing and Genomic Southern Blot Analysis. See Sup- ization was used to detect the expression of MBD1 and -gal mRNA. Both probes show strong hybridization in hippocampus. (b and c) Nissl staining of the brains porting Materials and Methods Ϫ Ϫ . of WT (b) and MBD1 / (c) mice. (Scale bar, 1.0 mm.) (d) X-Gal staining show- ing MBD1 expression pattern in the brains of MBD1ϩ/Ϫ (ϩ͞Ϫ) and MBD1Ϫ/Ϫ (Ϫ͞Ϫ) Karyotyping and Spectral Karyotyping (SKY) Analysis. Chromosome mice. X-Gal staining is negative in the brains of WT mice (ϩ͞ϩ). (e) High magni- spreads were made as described (27). Chromosome images were fication
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