Contribution to Society
Since nearly all biological phenomena are mediated by genes, gene targeting is impacting the analysis of nearly all aspects of mammalian biology, including studies in cancer, development, immunology, neurobiology and human disease. This technology has many implications for clinical medicine. Scientists can simulate a human genetic disease in laboratory models, study its development, and test potential therapies against it. In the future, however, since the investigator can choose which gene to modify and precisely how to modify it, therapies based on gene targeting will be used to correct the endogenous defective gene in the appropriate human tissue. These therapies will be directed at the cause rather than at the symptoms of the disease.
An immediate application of gene targeting to human medicine is to generate animal models for human disease such as cystic fibrosis, atherosclerosis, hypertension and cancer. These models provide a unique opportunity to undertake in-depth analysis of the pathology of human diseases, and they offer a means for developing new therapeutic protocols.
Research Summary
Our research efforts are directed towards the analysis of the developmental programs mediating pattern formation, organogenesis and neurogenesis in the mouse. Towards achieving these goals, we have pioneered the technology required for generating mutations in any gene in the mouse. This technology employs the exchange of DNA sequences, by homologous recombination, between exogenous, newly added DNA sequences and the cognate chromosomal DNA sequences in embryo-derived mouse stem (ES ) cells. This process is referred to as "gene-targeting". The ES cells containing the desired targeting event are then used to generate mouse germ line chimeras, capable of transmitting the mutation to their progeny. We are using this technology to determine the function of genes believed to mediate important developmental decisions in the mouse embryo. This technology is also being used to generate mouse models for human genetic diseases. Such animals allow a deeper analysis of the pathogenesis of the human disease, as well as provide appropriate subjects for testing new therapeutic protocols including somatic gene therapy. Eventually, this technology should also provide an avenue for directly correcting genetic defects in humans via somatic gene therapy.
Recent Publications
Wu, S., Y. Wu, M.R. Capecchi (2006). Motoneurons and oligodendrocytes are sequentially generated from neural stem cells but do not appear to share common lineage-restricted progenitors in vivo. Development 133, 581-590.
Keller, C., M. S. Hansen, C. M. Coffin and M. R. Capecchi (2004). Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin. Genes Dev. 18:2608-2613.
Keller , C., B. R. Arenkiel, C. M. Coffin, N. El-Bardeesy, R. A. DePinho and M. R. Capecchi (2004). Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev.18:2614-2626.
Boulet AM, Moon AM, Arenkiel BR and Capecchi MR (2004) The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Dev. Biol. 273, 361-372.
Arenkiel BR, Tvrdik P, Gaufo GO and Capecchi MR (2004) Hoxb1 functions in both motoneurons and tissues of the periphery to establish and maintain the proper neuronal circuitry. Genes Dev. 18, 1539-1552.
Gaufo GO, Wu S and Capecchi MR (2004) Contribution of Hox genes to the diversity of the hindbrain sensory system. Development 131, 1259-1266.
Boulet AM and Capecchi MR (2004) Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod. Development 131, 299-309.
Gaufo GO, Thomas KR and Capecchi MR (2003) Hox3 genes coordinate mechanisms of genetic suppression and activation in the generation of branchial and somatic motor neurons. Development 130, 5191-5201.
Vorbach C, Harrison R and Capecchi MR (2003) Xanthine oxidoreductase is central to the evolution and function of the innate immune system. Trends Immunol. 29, 512-517.
Wellik DM and Capecchi MR (2003) Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton. Science 301, 363-367.
Economides KR and Capecchi MR (2003) Hoxb13 is required for normal differentiation and secretory function of the ventral prostate. Development 130, 2061-2069.
Cole J, Khokhlova N, Sutliff RL, Adams JW, Disher KM, Zhao H, Capecchi MR, Corvol P and Bernstein KE (2003) Mice lacking endothelial angiotensin-converting enzyme (ACE): normal blood pressure with elevated angiotensin II. Hypertension 41, 313-321.
Economides KD, Zeltser L and Capecchi MR (2003) Hoxb13 mutations cause overgrowth of caudal spinal cord and tail vertebrae. Dev. Biol. 256, 317-330.
Schmidt EE, Bondareva AA, Radke JR and Capecchi MR (2003) Fundamental cellular processes do not require vertebrate-specific sequences within the TATA-binding protein. J. Biol. Chem. 278, 6168-6174.
Barrow JR, Thomas KR, Boussadia-Zahui O, Moore R, Kemler R, Capecchi MR, and McMahon AP (2003) Ectodermal Wnt3/?-catenin signaling is required for the establishment and the maintenance of the apical ectodermal ridge. Genes Dev. 17, 394-409.
Vorbach C, Scriven A and Capecchi MR (2002) The housekeeping gene Xanine Oxidoreductase is necessary for milk fat droplet enveloping and secretion: gene sharing in the lactating mammary gland. Genes Dev. 16, 3223-3235.
Frank DU, Fotheringham LK, Brewer JA, Muglia LJ, Tristani-Firouzi M, Capecchi MR and Moon AM (2002) An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development 129, 4591-4603.
Boulet AM and MR Capecchi (2002) Duplication of the Hoxd11gene causes alterations in the axial and appendicular skeleton of the mouse. Dev. Biol. 249, 96-107.
Hobbs NK, Bondareva AA, Barnett S, Capecchi MR and Schmidt EE (2002) Removing the vertebrate-specific TBP N-terminus disrupts placental ?2m-dependent interactions with the maternal immune system. Cell 110, 43-54.
Wellik DM, Hawkes PJ and Capecchi MR (2002) Hox11 paralogous genes are essential for metanephric kidney induction. Genes Dev. 16, 1423-1432.
Greer JM and Capecchi MR (2002) Hoxb8 is required for normal grooming behavior in the mouse. Neuron 33, 23-34.
Cole J, Quach DL, Sundaram K, Corvol P, Capecchi MR and Bernstein KE (2002) Mice lacking endothelial ACE have a normal blood pressure. Circ. Res. 90:87-92.
Capecchi MR (2001) Generating mice with targeted mutations. Nature Med. 7:1086-1090.
Capecchi MR (2001) Gene targeting: Altering the genome in mice. Ergito.
Stadler HS, Higgins KM and Capecchi MR (2001) Loss of Eph-receptor expression correlates with loss of cell adhesion and chondrogenic capacity in Hoxa13mutant limbs. Development 128, 4177-4188.
Manley NR, Barrow JR, Zhang T and Capecchi MR (2001) Hoxb2 and Hoxb4 act together to specify ventral body wall formation. Dev. Biol. 237:130-144.
Cole J, Ertoy D, Lin H, Sutliff RL, Ezan E, Guyene TT, Capecchi MR, Corvol P and Bernstein KE (2000) Mice deficient in angiotensin converting enzyme (ACE) have anemia due to a lack of angiotensin II facilitated erythropoiesis. J. Clin. Invest. 106:1391-1398.
Moon AM and Capecchi MR (2000) Fgf8 is required for outgrowth and patterning of the limbs. Nature Genet. 26: 455-459.
Gaufo GO, Flodby P and Capecchi MR (2000) Hoxb1 controls effectors of sonic hedgehog and Mash1 signaling pathways. Development 127: 5343-5354.
Schmidt EE, Taylor DS, Prigge JR, Barnett S and Capecchi MR (2000) Illegitimate Cre-dependent chromosome rearrangements in transgenic mouse spermatids. Proc. Natl. Acad. Sci. USA 97: 13702-13707.
Moon AM, Boulet AM and Capecchi MR (2000) Normal limb development in conditional mutants of Fgf4. Development 127:989-996.
Barrow JR, Stadler HS and Capecchi MR (2000) Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse. Development 127:933-944.
Greer JM, Puetz J, Thomas KR and Capecchi MR (2000) Maintenance of functional equivalence during paralogous Hox gene evolution. Nature 403:661-665.
Capecchi MR (2000) Human germline gene therapy: How and why. In Engineering the Human Germline. (G. Stock and J. Campbell, Eds.) New York: Oxford University Press, pp. 31-42.
Rossel M and Capecchi MR (1999) Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development 126:5027-5040.
Bunting M, Bernstein KE, Greer JR, Capecchi MR and Thomas KR (1999) Targeting genes for self-excision in the germline. Genes Dev. 13:1524-1528.
Godwin AR, Stadler HS, Nakamura K and Capecchi MR. (1998) Detection of targeted GFP-Hox gene fusions during mouse embryogenesis. Proc. Natl. Acad. Sci. USA 95:13042-13047.
Godwin AR and Capecchi MR (1998) Hoxc13 mutant mice lack external hair. Genes Dev. 12:11-20. |
