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CRISPR/Cas9 mediated knockout of rb1 and rbl1 leads to rapid and penetrant retinoblastoma development in Xenopus tropicalis

Thomas Naert (UGent) , Robin Colpaert, Tom Van Nieuwenhuysen (UGent) , Dionysia Dimitrakopoulou (UGent) , Jannick Leoen (UGent) , Jurgen Haustraete (UGent) , Annekatrien Boel (UGent) , Wouter Steyaert (UGent) , Trees Lepez (UGent) , Dieter Deforce (UGent) , et al.
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Abstract
Retinoblastoma is a pediatric eye tumor in which bi-allelic inactivation of the Retinoblastoma 1 (RB1) gene is the initiating genetic lesion. Although recently curative rates of retinoblastoma have increased, there are at this time no molecular targeted therapies available. This is, in part, due to the lack of highly penetrant and rapid retinoblastoma animal models that facilitate rapid identification of targets that allow therapeutic intervention. Different mouse models are available, all based on genetic deactivation of both Rb1 and Retinoblastoma-like 1 (Rbl1), and each showing different kinetics of retinoblastoma development. Here, we show by CRISPR/Cas9 techniques that similar to the mouse, neither rb1 nor rbl1 single mosaic mutant Xenopus tropicalis develop tumors, whereas rb1/rbl1 double mosaic mutant tadpoles rapidly develop retinoblastoma. Moreover, occasionally presence of pinealoblastoma (trilateral retinoblastoma) was detected. We thus present the first CRISPR/Cas9 mediated cancer model in Xenopus tropicalis and the first genuine genetic non-mammalian retinoblastoma model. The rapid kinetics of our model paves the way for use as a pre-clinical model. Additionally, this retinoblastoma model provides unique possibilities for fast elucidation of novel drug targets by triple multiplex CRISPR/Cas9 gRNA injections (rb1 + rbl1 + modifier gene) in order to address the clinically unmet need of targeted retinoblastoma therapy.
Keywords
GENOME, GENE, PRECLINICAL MODELS, TRILATERAL RETINOBLASTOMA, MICE, HEMATOPOIESIS, EXPRESSION, MANAGEMENT, ZEBRAFISH, DEFICIENT

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Chicago
Naert, Thomas, Robin Colpaert, Tom Van Nieuwenhuysen, Dionysia Dimitrakopoulou, Jannick Leoen, Jurgen Haustraete, Annekatrien Boel, et al. 2016. “CRISPR/Cas9 Mediated Knockout of Rb1 and Rbl1 Leads to Rapid and Penetrant Retinoblastoma Development in Xenopus Tropicalis.” Scientific Reports 6.
APA
Naert, T., Colpaert, R., Van Nieuwenhuysen, T., Dimitrakopoulou, D., Leoen, J., Haustraete, J., Boel, A., et al. (2016). CRISPR/Cas9 mediated knockout of rb1 and rbl1 leads to rapid and penetrant retinoblastoma development in Xenopus tropicalis. SCIENTIFIC REPORTS, 6.
Vancouver
1.
Naert T, Colpaert R, Van Nieuwenhuysen T, Dimitrakopoulou D, Leoen J, Haustraete J, et al. CRISPR/Cas9 mediated knockout of rb1 and rbl1 leads to rapid and penetrant retinoblastoma development in Xenopus tropicalis. SCIENTIFIC REPORTS. 2016;6.
MLA
Naert, Thomas, Robin Colpaert, Tom Van Nieuwenhuysen, et al. “CRISPR/Cas9 Mediated Knockout of Rb1 and Rbl1 Leads to Rapid and Penetrant Retinoblastoma Development in Xenopus Tropicalis.” SCIENTIFIC REPORTS 6 (2016): n. pag. Print.
@article{8150582,
  abstract     = {Retinoblastoma is a pediatric eye tumor in which bi-allelic inactivation of the Retinoblastoma 1 (RB1) gene is the initiating genetic lesion. Although recently curative rates of retinoblastoma have increased, there are at this time no molecular targeted therapies available. This is, in part, due to the lack of highly penetrant and rapid retinoblastoma animal models that facilitate rapid identification of targets that allow therapeutic intervention. Different mouse models are available, all based on genetic deactivation of both Rb1 and Retinoblastoma-like 1 (Rbl1), and each showing different kinetics of retinoblastoma development. Here, we show by CRISPR/Cas9 techniques that similar to the mouse, neither rb1 nor rbl1 single mosaic mutant Xenopus tropicalis develop tumors, whereas rb1/rbl1 double mosaic mutant tadpoles rapidly develop retinoblastoma. Moreover, occasionally presence of pinealoblastoma (trilateral retinoblastoma) was detected. We thus present the first CRISPR/Cas9 mediated cancer model in Xenopus tropicalis and the first genuine genetic non-mammalian retinoblastoma model. The rapid kinetics of our model paves the way for use as a pre-clinical model. Additionally, this retinoblastoma model provides unique possibilities for fast elucidation of novel drug targets by triple multiplex CRISPR/Cas9 gRNA injections (rb1 + rbl1 + modifier gene) in order to address the clinically unmet need of targeted retinoblastoma therapy.},
  articleno    = {35264},
  author       = {Naert, Thomas and Colpaert, Robin and Van Nieuwenhuysen, Tom and Dimitrakopoulou, Dionysia and Leoen, Jannick and Haustraete, Jurgen and Boel, Annekatrien and Steyaert, Wouter and Lepez, Trees and Deforce, Dieter and Willaert, Andy and Creytens, David and Vleminckx, Kris},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keyword      = {GENOME,GENE,PRECLINICAL MODELS,TRILATERAL RETINOBLASTOMA,MICE,HEMATOPOIESIS,EXPRESSION,MANAGEMENT,ZEBRAFISH,DEFICIENT},
  language     = {eng},
  pages        = {10},
  title        = {CRISPR/Cas9 mediated knockout of rb1 and rbl1 leads to rapid and penetrant retinoblastoma development in Xenopus tropicalis},
  url          = {http://dx.doi.org/10.1038/srep35264},
  volume       = {6},
  year         = {2016},
}

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