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Mario Capecchi

Distinguished Professor of Human Genetics and
Professor of Biology and
Adjunct Professor of Oncological SciencesMario Capecchi

2007 Nobel Prize Winner for Physiology or Medicine

B.S. Antioch College

Ph.D. Harvard University

Research

References

Mario Capecchi's Lab Page

Mario Capecchi's PubMed Literature Search

Molecular Biology Program

Mammalian Development, Human Pathology from Cancer to Neuropschiatric Disorders

Research

We have recently turned our attention to the role of microglia, the immune cell of the brain, in maintaining brain homeostasis and in protecting us from acquisition of anxiety disorders.  Anxiety disorders affect ~20% of adults.  These statistics are even more alarming for adolescents, with 38% of females and 26% of males reporting disabling anxiety.  The levels of anxiety disorders are currently rapidly arising even higher as a consequence of the COVID-19 pandemic.  The strong sex bias of anxiety disorders is observed at all age levels in humans.  We have shown in mice that a genetic disruption in a subpopulation of microglia (Hoxb8 microglia) causes chronic anxiety and, as in humans, females exhibit more severe pathology than males.  Moreover, the more severe pathology in females can be reduced to male levels by treatments that lowers their female hormone levels.  In contrast, the pathology in mutant males can be increased to female levels by the introduction of female hormones.  Since we can induce the behavioral pathologies through optogenetic stimulation we are positioned to map the brain circuitry that cause these disorders and determine how microglia communicate with specific brain neural circuits to modulate their output.

            Anxiety disorders show extremely high comorbidity with a number of neuropsychiatric disorders.  Why such high comorbidity exists has not been answered nor why different choices, such as major depression, OCD or schizophrenia are made.  Our mouse model shows very high comorbidity with OCD spectrum disorder.  Why?  Can this choice be changed?  Many questions can now be addressed genetically and molecularly and the tools to address these questions are here.

References

  1. Feng H, Hockin M, Zhang S, Capecchi M, Gale B, Sant H. (2020). Enhanced Chromosome Extraction From Cells Using a Pinched Flow Microfluidic Device. Biomed Microdevices2;22(2):25 PMID: 32166434

  2. Nam HS and Capecchi MR (2020). Lrig1 expression prospectively identifies stem cells in the ventricular-subventricular zone that are neurogenic throughout adult life. Neural Dev. 17;15(1):3
  3. Tränkner D, Boulet A, Peden E, Focht R, Capecchi M (2019). A microglia sublineage protects from sex-linked anxiety symptoms and obsessive compulsion. Cell Reports29(4):791-799 PMID: 31644903
  4. Patel N, Wang J, Shiozawa K, Jones KB, Zhang Y, Prokop JW, Davenport GG, Nihira NT, Hao Z, Wong D, Brandsmeier L, Meadows SK, Sampaio AV, Werff RV, Endo M, Capecchi MR, McNagny KM, Mak TW, Nielsen TO, Underhill TM, Myers RM, Kondo T, Su L. (2019). HDAC2 Regulates Site-Specific Acetylation of MDM2 and Its Ubiquitination Signaling in Tumor Suppression. iScience 13:43-54 PMID: 30818224

     

  5. Yu D, Wang J, Zou H, Feng T, Chen L, Li J, Qi X, Li Z, Duan X, Xu C, Zhang L, Long X, Lan J, Chen C, Wang C, Xu X, Ren J, Zhao Y, Hu X, Lian Z, Men H, Pan D, Li N, Capecchi MR, Du X, Zhao Y, Wu S. (2018). Silencing of retrotransposon-derived imprinted gene RTL1 is the main cause for postimplantational failures in mammalian cloning. Proc Natl Acad Sci USA PMID: 30381455

  6. De, S., D. Van Deren, E. Peden, M. Hockin, A. Boulet, S. Titen and M. Capecchi (2018).  Two Distinct Ontogenies Confer Heterogeneity to Brain Microglia.  Development 145 PMID: 29973370.

  7. Banito A, Li X, Laporte AN, Roe JS, Sanchez-Vega F, Huang CH, Dancsok AR, Hatzi K, Chen CC, Tschaharganeh DF, Chandwani R, Tasdemir N, Jones KB, Capecchi MR, Vakoc CR, Schultz N, Ladanyi M, Nielsen TO, Lowe SW (2018). The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. Cancer Cell 33:527-541 PMID: 29502955.

  8. Barrott JJ, Illum BE, Jin H, Hedberg ML, Wang Y, Grossmann A, Haldar M, Capecchi MR, Jones KB (2018). Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells. J Clin Invest 128:207-218 PMID: 29202462.

  9. Langer E.M., N.D Kendsersky, C.J. Daniel, G.M. Kuziel, C. Pelz, K.M. Murphy, M.R. Capecchi and R.C. Sears (2017). ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells. Oncogene. Oct 30. [Epub ahead of print] PMID: 29084210.

  10. Nagarajan N., B.W. Jones, P.J. West, R.E. Marc and M.R. Capecchi (2017). Corticostriatal circuit defects in Hoxb8 mutant mice. Mol Psychiatry Sep 26. [Epub ahead of print] PMID: 28948967.

  11. Barrott J.J., J.F. Zhu, K. Smith-Fry, A.M. Susko, D. Nollner, L.D. Burrell, A. Pozner, M.R. Capecchi, J.T. Yap, L.A. Cannon-Albright, X. Deng and K.B. Jones (2017). The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis. Mol Cancer Res15:1733-1740 PMID: 28851813.

  12. Ruff J.S., R.B. Saffarini, L.L. Ramoz, L.C. Morrison, S. Baker, S.M. Laverty, P. Tvrdik, M.R. Capecchi and W.K. Potts (2017). Mouse fitness measures reveal incomplete functional redundancy of Hox paralogous group 1 proteins. PLoS One. 12:e0174975. eCollection 2017. PMID: 28380068.

  13. Kim G., N. Nagarajan, E. Pastuzyn, K. Jenks, M. Capecchi, J. Shepherd and R. Menon (2017). Deep-brain imaging via epi-fluorescence Computational Cannula Microscopy. Sci Rep7:44791. PMID: 28317915.

  14. Li S., H. Lan, H. Men, Y. Wu, N. Li, M.R. Capecchi, E.C. Bryda and S. Wu (2017). Derivation of Transgene-Free Rat Induced Pluripotent Stem Cells Approximating the Quality of Embryonic Stem Cells. Stem Cells Transl Med. 6:340-351. PMID: 27625042.

  15. Zhang X., X. Wei, Y. Wu, Y. Wang, C. Tan, X. Hu, N. Li, M.R. Capecchi and S. Wu (2017). Genome-wide piggyBac transposon mediated screening reveals genes related to reprogramming. Protein Cell8:134-139. PMID: 27761808.

  16. Xu C., X. Qi, X. Du, H. Zou, F. Gao, T. Feng, H. Lu, S. Li, X. An, L. Zhang, Y. Wu, Y. Liu, N. Li, M.R. Capecchi and S. Wu (2017). piggyBac mediates efficient in vivo CRISPR library screening for tumorigenesis in mice.  Proc Natl Acad Sci USA114:722-727. PMID: 28062688.

  17. Barrott J.J., L.A. Kafchinski, H. Jin, J.W. Potter, S.D. Kannan, R. Kennedy, T. Mosbruger, W.L. Wang, J.W. Tsai, D.M. Araujo, T. Liu, M.R. Capecchi, A.J. Lazar and K.B. Jones (2016). Modeling synovial sarcoma metastasis in the mouse: PI3'-lipid signaling and inflammation. J Exp Med213:2989-3005. PMID: 27956588.

  18. Wu S., M. Mariotti, D. Santesmasses, K.E. Hill, J. Baclaocos, E. Aparicio-Prat, S. Li, J. Mackrill, Y. Wu, M.T. Howard, M. Capecchi, R. Guigó, R.F. Burk and J.F. Atkins (2016). Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements. Open Biol6. pii: 160241. PMID: 27881738.

  19. Lan H., S. Li, Z. Guo, H. Men, Y. Wu, N. Li, E.C. Bryda, M.R. Capecchi and S. Wu (2016). Efficient generation of selection-gene-free rat knockout models by homologous recombination in ES cells. FEBS Lett590:3416-3424. PMID: 27597178.

  20. Jones K.B., J.J. Barrott, M. Haldar, H. Jin, J.F. Zhu, M. Monument, E. Langer, R.L. Randall and M.R. Capecchi (2016).  The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis. Oncogene35:5021-32.

  21. Carroll, L.S. and Capecchi, M.R. (2015). HOXC8 initiates an ectopic mammary program by regulating Fgf10 and Tbx3 expression, and Wnt/β-catenin signaling. Development.142(23):4056-67.
  22. Prigge, J.R., Hoyt, T.R., Dobrinen, E., Capecchi, M.R., Schmidt, E.E., N. Meissner (2015). Type I IFNs Act upon Hematopoietic Progenitors to Protect and Maintain Hematopoiesis during Pneumocystis Lung Infection in Mice. J Immunol. 195(11):5347-57.
  23. Pozner, A. and Capecchi, M. (2015). ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination. Nature Communications.6:8763.
  24. Roux, M., Laforest, B., Capecchi, M., Bertrand, N., S. Zaffran (2015). Hoxb1 regulates proliferation and differentiation of second heart field progenitors in pharyngeal mesoderm and genetically interacts with Hoxa1 during cardiac outflow tract development. Dev Biol.406:2:247-58.
  25. Quist, T., Jin, H., Zhu, J., Smith-Fry, K., Capecchi, M.R. and K.B. Jones (2014). The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse. Oncogene. 34(32):4278-84.
  26. Pozner, A., Xu, B., Palumbos, S., Gee, J.M., Tvrdik, P., M.R. Capecchi (2015). Intracellular calcium dynamics in cortical microglia responding to focal laser injury in the PC::G5-tdT reporter mouse. Front Mol Neurosci.8:12.
  27. Gee, J.M., Gibbons, M.B., Taheri, M., Palumbos, S., Morris, S.C., Smeal, R.M., Flynn, K.F., Economo, M.N., Cizek, C.G., Capecchi, M.R., Tvrdik, P., Wilcox, K.S., J.A. White (2015). Imaging activity in astrocytes and neurons with genetically encoded calcium indicators following in utero electroporation. Front Mol Neurosci.8:10. eCollection 2015.
  28. Goodwin, M.L., Jin, H., Straessler, K., Smith-Fry, K., Zhu, J.F., Monument, M.J., Grossmann. A., Randall, R.L., Capecchi, M.R. and K.B. Jones (2014). Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment. Cancer Cell. 26(6):851-62.
  29. Haldar, M., Karan, G., Watanabe, S., Guenther, S. Braun, T. and M.R. Capecchi (2014). Responses: contributions of the myf5-independent lineage to myogenesis. Dev. Cell31(5) 539-41.
  30. Chojnowski, J.L., Masuda, K., Trau, H.A. Thomas, K., Capecchi, M.R. and N. R. Manley (2014). Multiple roles for HOXA3 in regulating thymus and parathyroid differentiation and morphogenesis. Dev.141:3697-3708.
  31. Gee, J.M., Smith, N.A., Fernandez, F.R., Economo, M.N., Brunert, D., Rothermel, M. Morris, S.C., Talbot, A. Palumbos, S., Ichida, J., Shepherd, J., West, P.J., Wachowiak, D.M., Capecchi, M.R., Wilcox, K. S. White, J. A., Tvrdik, P. (2014). Imaging Activity in Neurons and Glia with a Polr2a-based and Cre-dependent GCaMP5G-IRES-tdTomato Reporter Mouse. Neuron.83:1058-72.
  32. Wu, S., Y. Wu, X. Zhang, and M.R. Capecchi (2014). Efficient germ-line transmission obtained with transgene-free induced pluripotent stem cells. Proc Natl Acad Sci U S A.111(29):10678-83.
  33. Abraham, J., Nunez-Alvarez, Y., Hettmer, S., Carrio, E., Chen, H., Nishijo, K., Huang, E.T., Prajapati, S., Walker, R.L., Davis, S., Rebeles, J., Wiebush, H., McCleish, A.T., Hampton, S.T., Bjornson, C.R.R., Brack, A.S., Wagers, A.J., Rando, T.A., Capecchi, M.R., Marini, F.C., Ehler, B.R., Zarzabal, L.A., Goros, M.W., Michalek, J.E., Meltzer, P.S., Langenau, D.M., LeGallo, R.D., Mansoor, A., Chen, Y., Suelves, M., Rubin, B.P. and C. Keller (2014). Lineage of origin in rhabdomyosarcoma informs pharmacological response. Gen Dev.28:1578-1591.
  34. Kurokawa, S., S. Eriksson, K.L. Rose, S. Wu, A.K. Motley, S. Hill, V.P. Winfrey, W.H. McDonald, M.R. Capecchi, J.F. Atkins, E.S. Arnér, K.E. Hill, and R.F. Burk (2014). Sepp1(UF) forms are N-terminal selenoprotein P truncations that have peroxidase activity when coupled with thioredoxin reductase-1. Free Radic Biol Med.69:67-76.
  35. Jones, K.B., L. Su, H. Jin, C. Lenz, R.L. Randall, T.M. Underhill, T.O. Nielson, S. Sharma, and M.R. Capecchi (2013). SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas. Oncogene. 32(18):2365-71, 2375.e1-5.
  36. Straessler, K.M., K.B. Jones, H. Hu, H. Jin, M. van de Rijn, and M.R. Capecchi (2013). Modeling clear cell sarcomagenesis in the mouse: cell of origin differentiation state impacts tumor characteristics. Cancer Cell.23(2):215-27.
  37. Boulet, A.M. and M.R. Capecchi (2012). Signaling by FGF4 and FGF8 is required for axial elongation of the mouse embryo. Dev Biol.371(2):235-45.
  38. Makki, N. and M.R. Capecchi (2012). Cardiovascular defects in a mouse model of HOXA1 syndrome. Hum. Mol. Genet.21(91):26-31.
  39. Makki, N. and M.R. Capecchi (2011). Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development. Dev. Bio. 357(2):295-304.
  40. Makki, N. and M. R. Capecchi (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(2):499–509.
  41. Xue, H., S. Wu, S.T. Papadeau, S. Spusta, A.M. Swistowska, C.C. MacArthur, M.P. Mattson, N.J. Maragakis, M.R. Capecchi, M.S. Rao, S. Zeng, and Y. Liu (2009). A targeted neuroglial reporter line generated by homologous recombination in human embryonic stem cells. Stem Cell.27(8): 1836-46.
  42. Haldar, M., M. Hedberg, M. Hockin, and M.R. Capecchi (2009). A CreER based random induction strategy for modeling translocation-associated sarcomas in mice. Cancer Res.69(8):3657-64.
  43. Sangiorgi, E. and M.R. Capecchi (2008). Bmi1 lineage tracing identifies a self-renewing pancreatic acinar cell subpopulation capable of maintaining pancreatic organ homeostasis. PNAS.106(17):7101-7106.
  44. Ray, R. and M.R. Capecchi (2008). An examination of the chiropteran HoxD locus from an evolutionary perspective. Evol. & Dev.10(6):657-70.
  45. Sangiorgi, E., Z. Shuhua, and M.R. Capecchi (2008). In vivo evaluation of PhiC31 recombinase activity using a self-excision cassette. Nucleic Acids Res.36(20):e134.
  46. Capecchi, M.R. (2008). The Making of a Scientist II (Nobel Lecture). ChemBioChem9(10):1530-43.
  47. Sangiorgi, E. and M.R. Capecchi (2008). Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet. 40(7):915-20.
  48. Haldar, M., R.L. Randall, and M. R. Capecchi (2008). Synovial Sarcoma: From Genetics to Genetic-based Animal Modeling. Clin OrthopRelat Res.466(9):2156-67.
  49. Haldar, M. G. Karan, P. Tvrdik, and M.R. Capecchi (2008). Two cell lineages, Myf5-independent, participate in mouse skeletal myogenesis. Dev Cell.14(3):437-45.
  50. Wu, S., G. Ying, Q. Wu, and M.R. Capecchi (2008). A protocol for constructing gene targeting vectors: generating knockout mice for the cadherin family and beyond. Nat Protocols. 3(6):1056-76.to page top
Last Updated: 7/10/20