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Generation of Cerebral Cavernous Malformation in Neonatal Mouse Models Using Inducible Cre-LoxP Strategy

  • Jaesung P. ChoiEmail author
  • Xiangjian Zheng
Protocol
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Part of the Methods in Molecular Biology book series (MIMB, volume 2152)

Abstract

Mutations in the CCM1 (aka KRIT1), CCM2, or CCM3 (aka PDCD10) gene cause cerebral cavernous malformation (CCM) in humans. Neonatal mouse models of CCM disease have been established by deleting any one of the Ccm genes. These mouse models provide invaluable in vivo disease model to investigate molecular mechanisms and therapeutic approaches for the disease. Here, we describe detailed methodology to generate CCM disease in mouse models (Ccm1 and Ccm2-deficient) using inducible Cre/loxP recombination strategy.

Key words

Cerebral cavernous malformation CCM Mouse model Vascular malformation CCM1 KRIT1 CCM2 OSM Endothelial cells Cre/loxP 

Notes

Acknowledgments

These studies were supported by Kenyon Family Foundation Inflammation Award (JC), Be Brave for Life Micro-Grant Award (JC) and Australian National Health and Medical Research Council (NHMRC) project grant APP1124011 (XZ).

References

  1. 1.
    Al-Holou WN, O’Lynnger TM, Pandey AS, Gemmete JJ, Thompson BG, Muraszko KM, Garton HJ, Maher CO (2012) Natural history and imaging prevalence of cavernous malformations in children and young adults. J Neurosurg Pediatr 9(2):198–205.  https://doi.org/10.3171/2011.11.PEDS11390CrossRefPubMedGoogle Scholar
  2. 2.
    Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E (2005) Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76(1):42–51CrossRefGoogle Scholar
  3. 3.
    Denier C, Goutagny S, Labauge P, Krivosic V, Arnoult M, Cousin A, Benabid AL, Comoy J, Frerebeau P, Gilbert B, Houtteville JP, Jan M, Lapierre F, Loiseau H, Menei P, Mercier P, Moreau JJ, Nivelon-Chevallier A, Parker F, Redondo AM, Scarabin JM, Tremoulet M, Zerah M, Maciazek J, Tournier-Lasserve E (2004) Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 74(2):326–337CrossRefGoogle Scholar
  4. 4.
    Laberge-le Couteulx S, Jung HH, Labauge P, Houtteville JP, Lescoat C, Cecillon M, Marechal E, Joutel A, Bach JF, Tournier-Lasserve E (1999) Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 23(2):189–193CrossRefGoogle Scholar
  5. 5.
    Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, Verlaan D, Balogun F, Hughes L, Leedom TP, Plummer NW, Cannella M, Maglione V, Squitieri F, Johnson EW, Rouleau GA, Ptacek L, Marchuk DA (2003) Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73(6):1459–1464CrossRefGoogle Scholar
  6. 6.
    Sahoo T, Johnson EW, Thomas JW, Kuehl PM, Jones TL, Dokken CG, Touchman JW, Gallione CJ, Lee-Lin SQ, Kosofsky B, Kurth JH, Louis DN, Mettler G, Morrison L, Gil-Nagel A, Rich SS, Zabramski JM, Boguski MS, Green ED, Marchuk DA (1999) Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 8(12):2325–2333CrossRefGoogle Scholar
  7. 7.
    Boulday G, Rudini N, Maddaluno L, Blecon A, Arnould M, Gaudric A, Chapon F, Adams RH, Dejana E, Tournier-Lasserve E (2011) Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. J Exp Med 208(9):1835–1847.  https://doi.org/10.1084/jem.20110571CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chan AC, Drakos SG, Ruiz OE, Smith AC, Gibson CC, Ling J, Passi SF, Stratman AN, Sacharidou A, Revelo MP, Grossmann AH, Diakos NA, Davis GE, Metzstein MM, Whitehead KJ, Li DY (2011) Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice. J Clin Invest 121(5):1871–1881.  https://doi.org/10.1172/JCI44393CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    McDonald DA, Shenkar R, Shi C, Stockton RA, Akers AL, Kucherlapati MH, Kucherlapati R, Brainer J, Ginsberg MH, Awad IA, Marchuk DA (2011) A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease. Hum Mol Genet 20(2):211–222.  https://doi.org/10.1093/hmg/ddq433CrossRefPubMedGoogle Scholar
  10. 10.
    Zheng X, Riant F, Bergametti F, Myers CD, Tang AT, Kleaveland B, Pan W, Yang J, Tournier-Lasserve E, Kahn ML (2014) Cerebral cavernous malformations arise independent of the heart of glass receptor. Stroke 45(5):1505–1509.  https://doi.org/10.1161/STROKEAHA.114.004809CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Luthi U, Barberis A, Benjamin LE, Makinen T, Nobes CD, Adams RH (2010) Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465(7297):483–486.  https://doi.org/10.1038/nature09002CrossRefPubMedGoogle Scholar
  12. 12.
    Mleynek TM, Chan AC, Redd M, Gibson CC, Davis CT, Shi DS, Chen T, Carter KL, Ling J, Blanco R, Gerhardt H, Whitehead K, Li DY (2014) Lack of CCM1 induces hypersprouting and impairs response to flow. Hum Mol Genet 23(23):6223–6234.  https://doi.org/10.1093/hmg/ddu342CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zheng X, Xu C, Smith AO, Stratman AN, Zou Z, Kleaveland B, Yuan L, Didiku C, Sen A, Liu X, Skuli N, Zaslavsky A, Chen M, Cheng L, Davis GE, Kahn ML (2012) Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth. Dev Cell 23(2):342–355.  https://doi.org/10.1016/j.devcel.2012.06.004CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Centre for Inflammation, Centenary Institute, and Faculty of Science, University of Technology SydneySydneyAustralia
  2. 2.Laboratory of Cardiovascular Signalling, Centenary Institute, and Sydney Medical School, University of SydneyUniversity of SydneySydneyAustralia
  3. 3.Department of PharmacologySchool of Basic Medical Sciences, Tianjin Medical UniversityTianjinChina

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