Abstract
The timing of lethality caused by homozygosity for a null allele of the epidermal growth factor receptor (Egfrtm1Mag) in mice is strongly dependent on genetic background. Initial attempts to genetically map background modifiers using Swiss-derived, outbred CD-1 mice were unsuccessful. To investigate the genetic architecture contributing to survival of Egfrtm1Mag homozygous embryos, the genetic variability segregating within the outbred population was partitioned by surveying viability of Egfrtm1Mag mutants using intercrosses between 129S6/SvEvTAC-Egfrtm1Mag and nine Swiss-derived, inbred strains: ALR/LtJ, ALS/LtJ, APN, APS, ICR/HaRos, NOD/LtJ, NON/LtJ, SJL/J, and SWR/J. The observations showed that these strains support varying levels of survival of Egfrtm1Mag homozygous embryos, suggesting that genetic heterogeneity within the CD-1 stock contributed to the original lack of Egfrtm1Mag modifier detection. Similar to the Swiss-derived intercrosses, nine congenic strains, derived from 129S6/SvEvTAC, AKR/J, APN, BALB/cJ, BTBR-T+ tf/tf, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ inbred backgrounds, also supported varying levels of survival of Egfrtm1Mag mutants. By intercrossing the congenic lines to create hybrid F1 embryos, different genetic backgrounds were found to have complementary modifiers. Analysis of the congenic lines argues against heterosis of outbred backgrounds contributing to Egfrtm1Mag phenotypic variability. A detailed analysis of the crosses suggests that modifiers function at three distinct stages of development. One class of modifiers supports survival of Egfrtm1Mag homozygous embryos to mid-gestation, another class supports development through the mid-gestation transition from yolk-sac to placental-derived nutrient sources, and a third class supports survival through later stages of gestation. Data from microarray analysis using RNA from wild-type and Egfrtm1Mag mutant placentas support the existence of extensive genetic heterogeneity and suggest that it can be molecularly partitioned. This method should be generally useful to partition heterogeneity contributing to other complex traits.
Full Text
The Full Text of this article is available as a PDF (224.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alroy I., Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 1997 Jun 23;410(1):83–86. doi: 10.1016/s0014-5793(97)00412-2. [DOI] [PubMed] [Google Scholar]
- Arteaga Carlos L., Baselga Jose. Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: implications for drug development and practice. Clin Cancer Res. 2003 May;9(5):1579–1589. [PubMed] [Google Scholar]
- Beck J. A., Lloyd S., Hafezparast M., Lennon-Pierce M., Eppig J. T., Festing M. F., Fisher E. M. Genealogies of mouse inbred strains. Nat Genet. 2000 Jan;24(1):23–25. doi: 10.1038/71641. [DOI] [PubMed] [Google Scholar]
- Casley W. L., Menzies J. A., Mousseau N., Girard M., Moon T. W., Whitehouse L. W. Increased basal expression of hepatic Cyp1a1 and Cyp1a2 genes in inbred mice selected for susceptibility to acetaminophen-induced hepatotoxicity. Pharmacogenetics. 1997 Aug;7(4):283–293. doi: 10.1097/00008571-199708000-00003. [DOI] [PubMed] [Google Scholar]
- Ciardiello F., Kim N., Saeki T., Dono R., Persico M. G., Plowman G. D., Garrigues J., Radke S., Todaro G. J., Salomon D. S. Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7792–7796. doi: 10.1073/pnas.88.17.7792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dassonville O., Formento J. L., Francoual M., Ramaioli A., Santini J., Schneider M., Demard F., Milano G. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol. 1993 Oct;11(10):1873–1878. doi: 10.1200/JCO.1993.11.10.1873. [DOI] [PubMed] [Google Scholar]
- DeRisi J., Penland L., Brown P. O., Bittner M. L., Meltzer P. S., Ray M., Chen Y., Su Y. A., Trent J. M. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat Genet. 1996 Dec;14(4):457–460. doi: 10.1038/ng1296-457. [DOI] [PubMed] [Google Scholar]
- Elenius K., Paul S., Allison G., Sun J., Klagsbrun M. Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. EMBO J. 1997 Mar 17;16(6):1268–1278. doi: 10.1093/emboj/16.6.1268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Evans J. T., Hauschka T. S., Mittelman A. Differential susceptibility of four mouse strains to induction of multiple large-bowel neoplasms by 1,2-dimethylhydrazine. J Natl Cancer Inst. 1974 Mar;52(3):999–1000. doi: 10.1093/jnci/52.3.999. [DOI] [PubMed] [Google Scholar]
- Fondacci C., Alsat E., Gabriel R., Blot P., Nessmann C., Evain-Brion D. Alterations of human placental epidermal growth factor receptor in intrauterine growth retardation. J Clin Invest. 1994 Mar;93(3):1149–1155. doi: 10.1172/JCI117067. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fowler K. J., Walker F., Alexander W., Hibbs M. L., Nice E. C., Bohmer R. M., Mann G. B., Thumwood C., Maglitto R., Danks J. A. A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1465–1469. doi: 10.1073/pnas.92.5.1465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Graser R. T., Mathews C. E., Leiter E. H., Serreze D. V. MHC characterization of ALR and ALS mice: respective similarities to the NOD and NON strains. Immunogenetics. 1999 Jul;49(7-8):722–726. doi: 10.1007/s002510050673. [DOI] [PubMed] [Google Scholar]
- Grünwald Viktor, Hidalgo Manuel. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst. 2003 Jun 18;95(12):851–867. doi: 10.1093/jnci/95.12.851. [DOI] [PubMed] [Google Scholar]
- Higashiyama S., Abraham J. A., Miller J., Fiddes J. C., Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991 Feb 22;251(4996):936–939. doi: 10.1126/science.1840698. [DOI] [PubMed] [Google Scholar]
- Jansen R. C., Nap J. P. Genetical genomics: the added value from segregation. Trends Genet. 2001 Jul;17(7):388–391. doi: 10.1016/s0168-9525(01)02310-1. [DOI] [PubMed] [Google Scholar]
- Leiter E. H., Reifsnyder P. C., Flurkey K., Partke H. J., Junger E., Herberg L. NIDDM genes in mice: deleterious synergism by both parental genomes contributes to diabetogenic thresholds. Diabetes. 1998 Aug;47(8):1287–1295. doi: 10.2337/diab.47.8.1287. [DOI] [PubMed] [Google Scholar]
- Luetteke N. C., Phillips H. K., Qiu T. H., Copeland N. G., Earp H. S., Jenkins N. A., Lee D. C. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev. 1994 Feb 15;8(4):399–413. doi: 10.1101/gad.8.4.399. [DOI] [PubMed] [Google Scholar]
- Marquardt H., Hunkapiller M. W., Hood L. E., Todaro G. J. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science. 1984 Mar 9;223(4640):1079–1082. doi: 10.1126/science.6320373. [DOI] [PubMed] [Google Scholar]
- Miettinen P. J., Berger J. E., Meneses J., Phung Y., Pedersen R. A., Werb Z., Derynck R. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature. 1995 Jul 27;376(6538):337–341. doi: 10.1038/376337a0. [DOI] [PubMed] [Google Scholar]
- Perou C. M., Jeffrey S. S., van de Rijn M., Rees C. A., Eisen M. B., Ross D. T., Pergamenschikov A., Williams C. F., Zhu S. X., Lee J. C. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9212–9217. doi: 10.1073/pnas.96.16.9212. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rickman D. S., Bobek M. P., Misek D. E., Kuick R., Blaivas M., Kurnit D. M., Taylor J., Hanash S. M. Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res. 2001 Sep 15;61(18):6885–6891. [PubMed] [Google Scholar]
- Riese D. J., 2nd, Bermingham Y., van Raaij T. M., Buckley S., Plowman G. D., Stern D. F. Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta. Oncogene. 1996 Jan 18;12(2):345–353. [PubMed] [Google Scholar]
- Riese D. J., 2nd, Komurasaki T., Plowman G. D., Stern D. F. Activation of ErbB4 by the bifunctional epidermal growth factor family hormone epiregulin is regulated by ErbB2. J Biol Chem. 1998 May 1;273(18):11288–11294. doi: 10.1074/jbc.273.18.11288. [DOI] [PubMed] [Google Scholar]
- Rubin Grandis J., Melhem M. F., Gooding W. E., Day R., Holst V. A., Wagener M. M., Drenning S. D., Tweardy D. J. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998 Jun 3;90(11):824–832. doi: 10.1093/jnci/90.11.824. [DOI] [PubMed] [Google Scholar]
- Rusch V., Baselga J., Cordon-Cardo C., Orazem J., Zaman M., Hoda S., McIntosh J., Kurie J., Dmitrovsky E. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res. 1993 May 15;53(10 Suppl):2379–2385. [PubMed] [Google Scholar]
- Shing Y., Christofori G., Hanahan D., Ono Y., Sasada R., Igarashi K., Folkman J. Betacellulin: a mitogen from pancreatic beta cell tumors. Science. 1993 Mar 12;259(5101):1604–1607. doi: 10.1126/science.8456283. [DOI] [PubMed] [Google Scholar]
- Sibilia M., Wagner E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science. 1995 Jul 14;269(5221):234–238. doi: 10.1126/science.7618085. [DOI] [PubMed] [Google Scholar]
- Strachan L., Murison J. G., Prestidge R. L., Sleeman M. A., Watson J. D., Kumble K. D. Cloning and biological activity of epigen, a novel member of the epidermal growth factor superfamily. J Biol Chem. 2001 Jan 16;276(21):18265–18271. doi: 10.1074/jbc.M006935200. [DOI] [PubMed] [Google Scholar]
- Tewari K. S., Kyshtoobayeva A. S., Mehta R. S., Yu I. R., Burger R. A., DiSaia P. J., Fruehauf J. P. Biomarker conservation in primary and metastatic epithelial ovarian cancer. Gynecol Oncol. 2000 Aug;78(2):130–136. doi: 10.1006/gyno.2000.5837. [DOI] [PubMed] [Google Scholar]
- Threadgill D. W., Dlugosz A. A., Hansen L. A., Tennenbaum T., Lichti U., Yee D., LaMantia C., Mourton T., Herrup K., Harris R. C. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science. 1995 Jul 14;269(5221):230–234. doi: 10.1126/science.7618084. [DOI] [PubMed] [Google Scholar]
- Toyoda H., Komurasaki T., Uchida D., Takayama Y., Isobe T., Okuyama T., Hanada K. Epiregulin. A novel epidermal growth factor with mitogenic activity for rat primary hepatocytes. J Biol Chem. 1995 Mar 31;270(13):7495–7500. doi: 10.1074/jbc.270.13.7495. [DOI] [PubMed] [Google Scholar]
- Umekita Y., Ohi Y., Sagara Y., Yoshida H. Co-expression of epidermal growth factor receptor and transforming growth factor-alpha predicts worse prognosis in breast-cancer patients. Int J Cancer. 2000 Nov 20;89(6):484–487. doi: 10.1002/1097-0215(20001120)89:6<484::aid-ijc3>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
- Wayne M. L., McIntyre L. M. Combining mapping and arraying: An approach to candidate gene identification. Proc Natl Acad Sci U S A. 2002 Nov 1;99(23):14903–14906. doi: 10.1073/pnas.222549199. [DOI] [PMC free article] [PubMed] [Google Scholar]