Produção Nacional
Revisado por pares
Failure of human rhombic lip differentiation underlies medulloblastoma formation
2022; Nature Portfolio; Volume: 609; Issue: 7929 Linguagem: Inglês
10.1038/s41586-022-05215-w
ISSN1476-4687
AutoresLiam D. Hendrikse, Parthiv Haldipur, Olivier Saulnier, Jake Millman, Alexandria H. Sjoboen, Anders W. Erickson, Winnie Ong, Victor Gordon, Ludivine Coudière-Morrison, Audrey Mercier, Mohammad Shokouhian, Raúl A. Suárez, Michelle Ly, Stephanie Borlase, David S. Scott, Maria C. Vladoiu, Hamza Farooq, Olga Sirbu, Takuma Nakashima, Shohei Nambu, Yusuke Funakoshi, Alec Bahcheli, J. Javier Díaz-Mejía, Joseph Golser, Kathleen Bach, Tram Phuong-Bao, Patryk Skowron, Evan Y. Wang, Sachin Kumar, Polina Balin, Abhirami Visvanathan, John J. Y. Lee, Ramy Ayoub, Xin Chen, Xiaodi Chen, Karen Mungall, Betty Luu, Pierre Bérubé, Yu C. Wang, Stefan M. Pfister, Seung-Ki Kim, Olivier Delattre, Franck Bourdeaut, François Doz, Julien Masliah‐Planchon, Wiesława Grajkowska, James Loukides, Peter B. Dirks, Michelle Fèvre‐Montange, Anne Jouvet, Pim J. French, Johan M. Kros, Karel Zitterbart, Swneke D. Bailey, Charles G. Eberhart, Amulya A. Nageswara Rao, Caterina Giannini, James M. Olson, Miklós Garami, Péter Hauser, Joanna J. Phillips, Stephanie Young, Carmen de Torres, Jaume Mora, Kay K. W. Li, Ho‐Keung Ng, Wai Sang Poon, Ian F. Pollack, Enrique López‐Aguilar, G. Yancey Gillespie, Timothy Van Meter, Tomoko Shofuda, Rajeev Vibhakar, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Toshihiro Kumabe, Shin Jung, Bolesław Lach, Achille Iolascon, Veronica Ferrucci, Pasqualino de Antonellis, Massimo Zollo, Giuseppe Cinalli, Shenandoah Robinson, Duncan Stearns, Erwin G. Van Meir, Paola Porrati, Gaetano Finocchiaro, Maura Massimino, Carlos Gilberto Carlotti, Cláudia C. Faria, Martine F. Roussel, Frederick A. Boop, Jennifer A. Chan, Kimberly A. Aldinger, Ferechté Razavi, Evelina Silvestri, Roger E. McLendon, Eric M. Thompson, Marc Ansari, Maria Luisa Garrè, F Chico, Pilar Eguía, Mario Pérezpeña-Díazconti, A. Sorana Morrissy, Florence M.G. Cavalli, Xiaochong Wu, Craig Daniels, Jeremy N. Rich, Steven J.M. Jones, Richard A. Moore, Marco A. Marra, Xi Huang, Jüri Reimand, Poul H. Sorensen, Robert J. Wechsler‐Reya, William A. Weiss, Trevor J. Pugh, Livia Garzia, Claudia L. Kleinman, Lincoln Stein, Nada Jabado, David Malkin, Olivier Ayrault, Jeffrey A. Golden, David W. Ellison, Bradley W. Doble, Vijay Ramaswamy, Tamra E. Werbowetski‐Ogilvie, Hiromichi Suzuki, Kathleen J. Millen, Michael D. Taylor,
Tópico(s)Fetal and Pediatric Neurological Disorders
ResumoMedulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
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