Genetic control of medulloblastoma formation

Research summary:

Medulloblastoma is the most common malignant brain tumor in children. Patients who survive medulloblastoma treatment often suffer cognitive deficits and have a tendency to develop other cancers later in life. Improved treatment is likely to come from a deeper understanding of signals controlling normal development of the rhombic lip neural stem cells giving rise to medulloblastoma. It shall allow the appreciation of developmental regulatory mechanisms susceptible to impede on embryonic medulloblastoma regionalized formation. 

Into this aim, we developed several mouse models to study this process in vivo. We are especially using either (i) embryos electroporated in utero with chosen constructs allowing Shh signaling overexpression, (ii) transgenic engineered mouse using the Cre/lox technology for conditional expression of SmoM2 (hyperactivated form of the Shh receptor Smoothened) previously found to induce Shh MB-like tumor formation, (iii) other TVA expressing mice designed to allow efficient RCAS viruses-mediated targeting of Shh or SmoM2 expression into the developing rhombic lip neural stem cells, either in embryos or in postnatal mouse.

Besides, we identified several homeobox containing transcription factors acting as master rhombic lip developmental regulators and susceptible to display some related pro- and anti-tumor in Shh medulloblastoma. We currently used our models to test and decipherer their functional interactions especially during the initial steps of Shh-dependent medulloblastoma formation, which stay largely mis-understood.


Fig 1. Formación de meduloblastoma dependiente de Shh en uno de nuestros modelos de ratones transgénicos expresando SmoM2 (B, caso control en A).


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Relevant publications:

  • El Nagar S, Chakroun A, Le Greneur C, Figarella-Branger D, Di Meglio T, Lamonerie T, Billon N. - Otx2 promotes granule cell precursor proliferation and Shh-dependent medulloblastoma maintenance in vivo. - Oncogenesis. - 2018 Aug 13
  • Karmakar K, Narita Y, Fadok J, Ducret S, Loche A, Kitazawa T, Genoud C, Di Meglio T, Thierry R, Bacelo J, Lüthi A, Rijli FM. - Hox2 Genes Are Required for Tonotopic Map Precision and Sound Discrimination in the Mouse Auditory Brainstem. - Cell Rep.- 2017 Jan 3
  • Di Meglio T, Kratochwil CF, Vilain N, Loche A, Vitobello A, Yonehara K, Hrycaj SM, Roska B, Peters AH, Eichmann A, Wellik D, Ducret S, Rijli FM. - Ezh2 orchestrates topographic migration and connectivity of mouse precerebellar neurons. - Science. 2013 Jan 11

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