MARIO R. CAPECCHI

Mario Capecchi
e-mail: capecchi@genetics.utah.edu
Distinguished Professor of Biology and Human Genetics
Investigator of the Howard Hughes Institute

Capecchi lab
Neurobiology of Disease
Developmental Neuroscience
B.S. 1961, Antioch College; Ph.D. 1967, Harvard University

RESEARCH:

Modeling neuropsychiatric disorders in the mouse

Homologous recombination between DNA sequences residing in the chromosome and newly introduced DNA sequences, termed gene targeting, provides the means for specifically modifying any gene in any desired manner in cultured mammalian cells. If the recipient cell for modification is a pluripotent, mouse embryo-derived stem cell, then the means are available for creating chimeric mice from these cells that will transfer the altered gene to their progeny. With this technology, the biological function of any cloned gene can be determined in the living mouse.

Dr. Capecchi is using this technology to genetically dissect neurogenesis, behavior, and neuropsychiatric disorders in the mouse.

Selected Publications:

Bertrand, N., Roux, M., Ryckebüsch, L., Niederreither, K., Dollé, P., Moon, A., Capecchi, M.R., and Zaffran, S. (2011) Hox genes define distinct progenitor sub-domains within the second heart field. Dev. Biol., 363(2):266-274.

Angus-Hill, M.L., Elbert, K.M., Hidalgo, J., and Capecchi M.R. (2011) T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis. PNAS, 108(12):4914-4919. 

Rubin, B.P., Nishijo, K., Chen, H.I., Yi, X., Schuetze, D.P., Pal, R., Prajapati, S.I., Abraham, J., Arenkiel, B.R., Chen, Q.R., Davis, S., McCleish, A.T., Capecchi, M.R., Michalek, J.E., Zarzabal, L.A., Khan, J., Yu, Z., Parham, D.M., Barr, F.G., Meltzer, P.S., Chen, Y., and Keller, C. (2011) Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. Cancer Cell, 19(2):177-191.

Guo, T., Mandai, K., Condie, B.G., Wickramasinghe, S.R., Wang, F., Capecchi, M.R., and Ginty, D.D.  (2011) An evolving NGF-Hoxd1 signaling pathway controls divergent neural circuit development in vertebrates. Nature Neurosci, 14(1):31-36.

Rollins, M.F., van der Heide, D.M., Weisend, C.M., Kundert, J.A., Constock, K.M., Suvorova, E.S., Capecchi, M.R., Merrill, G.F., and Schimdt, E.E. (2010) Hepatocytes lacking thioredoxin reductase 1 have normal replicative potential during development and regeneration. J. Cell Sci. 123:2402-2412.

Chen, S.C., Tvrdik, P., Peden, E., Cho, S., Wu, S., Spangrude, G., and Capecchi, M.R. (2010) Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice. Cell, 141(5):775-785.

Makki, N. and Capecchi, M.R. (2010) Hoxa1 linage-tracing indictes a direct role for Hoxa1 in development of the inner ear, the heart and the third rhombomere. Dev Bio., 341:499–509.

Jones, K.B., Piombo, V., Searby, C., Kurringer, G., Yang, B., Grabellus, F., Roughley, P., Morcuende, J., Buckwalter, J., Capecchi, M.R., Vortkamp, A., and Sheffield, V.C. (2010) A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondroytes. PNAS, 107(5):2054-2059. Epub 2009 Dec 22.

Xue, H., Wu, S., Papadeau, S.T., Spusta, S., Swistowska, A.M., MacArthur, C.C., Mattson, M.P., Maragakis, N.J., Capecchi, M.S., Rao, M.R., Zeng, S., and Liu, Y. (2009) A targeted neuroglial reporter line generated by homologous recombination in human embryonic stem cells. Stem Cell, 27(8):1836-1846.

Haldar, M., Hedberg, M., Hockin, M., and Capecchi, M.R. (2009) A CreER based random induction strategy for modeling translocation-associated sarcomas in mice. Cancer Res., 15:69(8):3657-3664.

Sangiorgi, E. and Capecchi, M.R. (2009) Bmi1 lineage tracing identifies a self-renewing pancreatic acinar cell subpopulation capable of maintaining pancreatic organ homeostasis. PNAS, Apr:106(17):7101-7106.

Ootani, A., Li, X., Sangiorgi, E., Ho, Q.T., Ueno, H., Toda, S., Sugihara, H., Fujimoto, K., Weissman, I.L., Capecchi, M.R., and Kuo, C.J. (2009) Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med., 5(6): 701-706 Epub Apr 27.

Nishijo, K., Hosoyama, T., Bjornson, C.R.R., Schaffer, B.S., Prajapati, S.I., Bahadur, A.N., Hansen, M.S., Blandford, M.C., McCleish, A.T., Rubin, B.P., Epstein, J.A., Rando, T.A., Capecchi, M.R. and Keller, C. (2009) Biomarker system for studying muscle, stem cells, and cancer in vivo. FASEB, 23(8): 2681-2690 Epub Mar 30.

Ying, G., Wu, S., Hou, R., Huang, W., Capecchi, M.R., and Wu, Q. (2009) The protocadherin gene Celsr3 is required for interneuron migration in the mouse forebrain. Mol. Cell. Biol., 29(11):3056-3061 Epub Mar 30.

Ray, R., and Capecchi, M.R. (2008) An examination of the chiropteran HoxD locus from an evolutionary perspective. Evol. & Dev., 10(6):657-670.

Kundert, J.A., Sealey, A.L., Li, Y., Capecchi, M.R., and Schmidt, E.E. (2008) Syngeneic immune-dependent abortions in mice suggest paternal alloantigen-independent mechanisms. Am. J. Reprod. Immunol., 60(4):290-297.

Capecchi, M.R. (2008) The Making of a Scientist II (Nobel Lecture). ChemBioChem Jul 2;9(10):1530-1543. Epub Jun 13.

Sangiorgi, E., and Capecchi, M.R. (2008) Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet, Jul;40(7):915-920.

Haldar, M., Randall, R.L., and Capecchi, M.R. (2008) Synovial Sarcoma: From Genetics to Genetic-based Animal Modeling. Clin OrthopRelat Res, Sep;466(9):2156-2167.

Haldar, M., Karan, G., Tvrdik, P., and Capecchi, M.R. (2008) Two cell lineages, Myf5-independent, participate in mouse skeletal myogenesis. Dev Cell, Mar(3)14:437-445.

Wu, S., Ying, G., Wu, Q., and Capecchi, M.R. (2008) A protocol for constructing gene targeting vectors: generating knockout mice for the cadherin family and beyond. Nat Protocols, 3(6):1056-1076.

Wu, Y., G. Wang, S.A. Scott, and M.R. Capecchi (2008) Hoxc10 and Hoxd10 regulate mouse columnar, divisional, and motor pool identity of lumbar motoneurons. Development, 135(1):171-182.

Tvrdik, P., and Capecchi, M.R. (2006) Reversal of Hox1 gene subfunctionalization in the mouse. Dev Cell., Aug;11(2):239-250.

Wu, S., Wu, Y., and Capecchi, M. R. (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.

Vorbach, C., Capecchi, M. R., and Penninger, J. M. (2006) Evolution of the mammary gland from the innate immune system? Bioessays, Jun;28(6):606-616.

Keller, C. B., and Capecchi, M. R. (2005) New Genetic Tactics to Model Alveolar Rhabdomyosarcoma in the Mouse. Cancer Res., Sept. 1; 65(17):7530-7532.

Kindlmann G. L., Weinstein, D. M., Jones, G. M., Johnson, C. R., Capecchi, M. R., and Keller, C. (2005) Practical vessel imaging by computed tomography in live transgenic mouse models for human tumors. Molecular Imaging, Oct-Dec;4(4):417-424.

Xiao, H. D., Fuchs, S., Campbell, D. J., Lewis, W., Dudley, S. C., Jr., Kasi, V. S., Hoit, B. D., Keshelava, G. T., Zhao, H., Capecchi, M. R., and Bernstein, K. E. (2004) Mice with cardiac restricted angiotensin converting enzyme (ACE) have atrial enlargement and sudden death. Am. J. Path., 165:1019-1032.

Keller, C., Hansen, M. S., Coffin, C. M., and Capecchi, M. R. (2004) Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin. Genes Dev., 18:2608-2613.

Keller, C., Arenkiel, B. R., Coffin, C. M., El-Bardeesy, N., DePinho, R. A., and Capecchi, M. R. (2004) Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev. 18:2614-2626.

Boulet, A. M., Moon, A. M., Arenkiel, B. R., and Capecchi, M. R. (2004) The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Dev. Biol., 273:361-372.

Arenkiel, B. R., Tvrdik, P., Gaufo, G. O., and Capecchi, M. R. (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, G. O., Wu, S., and Capecchi, M. R. (2004) Contribution of Hox genes to the diversity of the hindbrain sensory system. Development, 131:1259-1266.

Gaufo, G. O., Thomas, K. R., and Capecchi, M. R. (2003) Hox3 genes coordinate mechanisms of genetic suppression and activation in the generation of branchial and somatic motor neurons. Development, 130:5191-5201.

Wellik, D. M., and Capecchi, M. R. (2003) Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton. Science, 301:363-367.

Arenkiel, B. R., Gaufo, G. O., and Capecchi, M. R. (2003) Hoxb1 neural crest preferentially form glia of the PNS. Dev. Dynamics, 227:379-386.

Wellik, D. M., Hawkes, P. J., and Capecchi, M. R. (2002) Hox11 paralogous genes are essential for metanephric kidney induction. Genes Dev., 16:1423-1432.

Vorbach, C., Scriven, A., and Capecchi, M. R. (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.

Hobbs, N. K., Bondareva, A. A., Barnett, S., Capecchi, M. R., and Schmidt, E. E. (2002) Removing the vertebrate-specific TBP N-terminus disrupts placental b2m-dependent interactions with the maternal immune system. Cell, 110:43-54.

Greer, J. M., and Capecchi, M. R. (2002) Hoxb8 is required for normal grooming behavior in the mouse. Neuron 33:23-34.

Capecchi, M. R. (2001) Generating mice with targeted mutations. Nature Med., 7:1086-1090.

Moon, A. M., and Capecchi, M. R. (2000) Fgf8 is required for outgrowth and patterning of the limbs. Nature Genet. 26:455-459.

Gaufo, G. O., Flodby, P., and Capecchi, M. R. (2000) Hoxb1 controls effectors of sonic hedgehog and Mash1 signaling pathways. Development127:5343-5354.

Schmidt, E. E., Taylor, D. S., Prigge, J. R., Barnett, S., and Capecchi, M. R. (2000) Illegitimate Cre-dependent chromosome rearrangements in transgenic mouse spermatids. Proc. Natl. Acad. Sci. USA 97:13702-13707.

Barrow, J. R., Stadler, H. S., and Capecchi, M. R. (2000) Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse. Development 127:933-944.

Greer, J. M., Puetz, J., Thomas, K. R., and Capecchi, M. R. (2000) Maintenance of functional equivalence during paralogous Hox gene evolution. Nature 403:661-665.

Rossel, M., and Capecchi, M. R. (1999) Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development. Development 126:5027-5040.

Capecchi, M. R. (1997) The role of Hox genes in hindbrain development. In: Molecular and Cellular Approaches to Neural Development. (W.M. Cowan, T.M. Jessell and S.L. Zipursky, Eds.) New York: Oxford University Press. pp. 334-355.

Goddard, J. M., Rossel, M., Manley, N. R., and Capecchi, M. R. (1996) Mice with targeted disruption of Hoxb-1 fail to form the motor nucleus of the VIIth nerve. Development 122:3217-3228.

Davis, A. P., Witte, D. P., Hsieh-Li, H. M., Potter, S. S., and Capecchi, M. R. (1995) Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11. Nature 375:791-796.

Condie, B. G., and Capecchi, M. R. (1994) Mice with targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 reveal synergistic interactions. Nature 370:304-307.

Capecchi, M. R. (1994) Targeted gene replacement. Sci. Am. 270:54-61.