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Brca2 Is Required for Embryonic Cellular Proliferation in the Mouse

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Brca2 Is Required for Embryonic Cellular Proliferation in the Mouse Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Brca2 is required for embryonic cellular proliferation in the mouse Akira Suzuki, 1'2'6 Jos6 Luis de la Pompa, 1'2'6 RazqaUah Hakem, 1'2 Andrew Elia, 1'2 Ritsuko Yoshida, 1'2 Rong Mo, 3'4 Hiroshi Nishina, 1'2 Tony Chuang, 1'2 Andrew Wakeham, ~'2 Annick Itie, ~'2 Wilson Koo, ~'2 Phyllis Billia, ~'2 Alexandra Ho, 1'2 Manabu Fukumoto, 5 Chi Chung Hui, 3'4 and Tak W. Mak 1'2"7 1Amgen Institute, Toronto, Ontario, Canada M5G 2C1; 2Ontario Cancer Institute, Department of Medical Biophysics and Immunology, 3Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada; 4program in Developmental Biology and Division of Endocrinology Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8; SDepartment of Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 606 Mutations of the tumor suppressor gene BRCA2 are associated with predisposition to breast and other cancers. Homozygous mutant mice in which exons 10 and 11 of the Brca2 gene were deleted by gene targeting (Brca2 I°-11) die before day 9.5 of embryogenesis. Mutant phenotypes range from severely developmentally retarded embryos that do not gastrulate to embryos with reduced size that make mesoderm and survive until 8.5 days of development. Although apoptosis is normal, cellular proliferation is impaired in Brca2 ~°-H mutants, both in vivo and in vitro. In addition, the expression of the cyclin-dependent kinase inhibitor p21 is increased. Thus, Brca2 l°-H mutants are similar in phenotype to Brcal 5-6 mutants but less severely affected. Expression of either of these two genes was unaffected in mutant embryos of the other. This study shows that Brca2, like Brcal, is required for cellular proliferation during embryogenesis. The similarity in phenotype between Brcal and Brca2 mutants suggests that these genes may have cooperative roles or convergent functions during embryogenesis. IKey Words: Brca2 mutant mice; proliferation; embryogenesis; p21] Received March 26, 1997; revised version accepted April 14, 1997. The control of cell proliferation is achieved through a In the breast, the observation that endocrine factors that balance between negative and positive regulators of control breast development (Kleinberg and Newman growth (for review, see Hunter 1997). Tumor suppressors 1986) also influence breast cancer risk (Siiteri et al. 1986) are negative regulators of growth, and genetic lesions suggests that mammary gland development and carcino- that inactivate them release the cells from normal genesis are processes that are fundamentally related. growth constraints, causing the deregulated proliferation BRCA2 is a breast cancer susceptibility gene recently of cancer cells. Loss of growth control is accompanied by isolated by positional cloning (Wooster et al. 1995). Mu- alterations in normal pathways of differentiation and de- tations in BRCA2 are thought to account for as many as velopment. Tumor suppressor genes have been shown to 35% of all inherited breast cancers, as well as a propor- encode proteins involved in growth control and DNA tion of inherited ovarian cancers (Wooster et al. 1995; repair processes. Germ-line mutations in tumor suppres- Tavtigian et al. 1996). Like BRCA1, BRCA2 appears to be sor genes such as p53 (Malkin et al. 1990; Srivastava et a tumor suppressor gene, because the loss of the wild- al. 1990), Wilms' tumor (WT1)(Gessler et al. 1990), and type BRCA2 allele in heterozygous carriers can result in retinoblastoma (RB) (Hansen et al. 1985) are associated the development of tumors (Collins et al. 1995; Gud- with inherited predispositions to cancer. Targeted muta- mundsson et al. 1995). Few somatic mutations in either tion of these genes in mice causes cancer susceptibility BRCA1 (Futreal et aI. 1994) or BRCA2 (Miki et al. 1996) but also results in abnormalities in cellular proliferation have been identified in sporadic breast tumors, but germ- and differentiation and embryonic development (Done- line mutations in both BRCA1 (Miki et al. 1994) and hower et al. 1992; Lee et al. 1992; Kreidberg et al. 1993). BRCA2 (Phelan et al. 1986) predispose carriers to breast adenocarcinoma. However, unlike BRCA1, germ-line mutations in BRCA2 predispose both males and females to breast cancer, and female carriers of BRCA2 germ-line mutations show a lower incidence of ovarian cancer than 6These authors contributed equally to this work. 7Corresponding author. do BRCA1 carriers (Thorlacius et al. 1995; Wooster et al. E-MAIL [email protected]; FAX (416) 204-5300. 1995). 1242 GENES & DEVELOPMENT 11:1242-1252 © 1997 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/97 $5.00 Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Brca2 in murine embryonic cellular proliferation The BRCA2 gene consists of 27 exons that generate an duce homozygous mutant offspring. The genotypes of 11-kb mRNA transcript predicted to encode a novel pro- the mice were confirmed by Southern blot analysis. tein of 3418 amino acids (Tavtigian et al. 1996). Interest- ingly, the BRCA1 and BRCA2 genes are similar in several Phenotype of heterozygous Brca2 ~°-1~ mice respects, despite a marked lack of nucleotide or amino acid sequence homology. Both BRCA1 and BRCA2 are large Mice heterozygous for the Brca2 ~°-~ deletion were phe- AT-rich genes, which include an exon of unusually large notypically normal and fertile. Heterozygous Brca2 ~°-~1 size. Neither gene shows homology to any known protein. mice did not develop any type of cancer up to 7 months The numerous germ-line mutations that have been iden- of age. It remains possible, however, that Brca2 ~°-~ ~ het- tified in both BRCA1 and BRCA2 are distributed through- erozygotes could develop tumors at a more advanced age. out their lengths, and most of them result in protein trun- cation (Gayther et al. 1997). In addition, the spatial and Brca21°-~ 1 mutation results in embryonic lethality temporal pattern of Brca2 mRNA expression in the mouse is strikingly similar to that of Brcal during fetal develop- No viable Brca2 I°-~l pups were identified among 51 ment, and in adult tissues in vivo and in mammary epi- offspring born form heterozygous intercrosses, indicat- thelial cells in vitro (Rajan et al. 1996). Both Brcal and ing that homozygosity for the Brca21°-~ mutation Brca2 are expressed in a cell cycle-dependent manner, causes embryonic lethality (Fig 1B; Table 1). To assess peaking at the G~/S boundary. Nevertheless, because there the consequences of the Brca2 ~°-~ mutation on embry- are no obvious extended regions of nucleotide or amino onic development, we analyzed embryos from heterozy- acid homology between BRCA1 and BRCA2, whether gote intercrosses at different days of gestation (Table 1). these similarities reflect an underlying structural or func- Genomic DNA was isolated from yolk sacs or from tional homology remains to be determined. Taken to- whole embryos, and genotyping was performed by PCR gether, the available data suggest that Brcal and Brca2 may amplification using primers a-d (Fig. 1A, C). At embry- function in overlapping regulatory pathways involved in onic day 6.5 (E6.5) -25% of all embryos were morpho- the control of cell proliferation and differentiation (Rajan et logically abnormal; these were genotyped as mutants. al. 1996, and unpubl.; Vaughn et al. 1996). E6.5 Brca2 ~°-~ mutant embryos were half the size of To determine the role of Brca2 in embryonic develop- their wild-type E6.5 littermates and showed a poorly de- ment and adult cellular physiology, we have generated a fined boundary between the embryonic and the extraem- Brca2-deficient mouse by targeted deletion of exons 10- bryonic regions (Fig. 2A). At E7.5, the difference in size 11 of the Brca2 gene. Heterozygous Brca21°-~ mutant between wild-type and mutant embryos was even more mice are viable and normal, but homozygous Brca2 ~°-~ dramatic (Fig. 2B), and some mutant embryos had com- mutant embryos die during early postimplantation de- menced resorption. At E8.5, most mutant embryos were velopment. Analysis of Brca2 ~°-~ mutant embryos in in resorption (Table 1), although some did develop a head vivo and in vitro indicates that Brca2 is essential for the fold, a primordial neural tube, allantois, and expanded control of the proliferative process that occurs in early yolk sac but no somites (Fig. 2C). All mutant embryos embryonic development. The similarities and differences were dead or in resorption by E9.5. in phenotype between the Brcal and Brca2 mutants, and Mutant mice generated from the two independent tar- their possible functional relationship, are discussed. geted ES cell clones showed identical phenotypes. In ad- dition, the analyses were performed in both an inbred (C57BL/6J) and an outbred (CD1)background that gave Results comparable phenotypes. These results demonstrate that homozygosity for the Brca2 ~°-~ ~ allele results in embry- Generation of Brca2 ~°-1 ~ mutant mice onic lethality before E9.5 and indicate that Brca2 is es- The Brca2 gene was disrupted in embryonic stem (ES) sential for postimplantation development. cells using a targeting vector that deleted the 3' half of exon 10 and the 5' half of exon 11 of Brca2, leading to the Histological analysis of the Brca21°-11 mutant introduction of two termination codons in-frame. A cas- embryos sette containing the neomycin resistance (neo) gene with the phosphoglycerokinase (PGK) promoter and a poly(A) The structural organization of Brca21°-11 mutant em- addition signal was inserted in the sense orientation in bryos was characterized in detail by histological analysis the targeting vector, so that the short arm consisted of of serially sectioned E5.5-E7.5 embryos obtained from 516 bp of exon 10 and the long arm contained 5.0 kb of heterozygous crosses (Fig. 3A-H). Differences in size be- exon 11 (Fig.
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