The transition of neural progenitors to differentiated postmitotic neurons is mainly considered irreversible in physiological conditions. In the present work, we show that Shh pathway activation through SmoM2 expression promotes postmitotic neurons dedifferentiation, re-entering in the cell cycle and originating medulloblastoma in vivo. Notably, human adult patients present inactivating mutations of the chromatin reader BRPF1 that are associated with SMO mutations and absent in pediatric and adolescent patients. Here, we found that truncated BRPF1 protein, as found in human adult patients, is able to induce medulloblastoma in adult mice upon SmoM2 activation. Indeed, postmitotic neurons re-entered the cell cycle and proliferated as a result of chromatin remodeling of neurons by BRPF1. Our model of brain cancer explains the onset of a subset of human medulloblastoma in adult individuals where granule neuron progenitors are no longer present.

Truncated BRPF1 cooperates with smoothened to promote adult shh medulloblastoma / Aiello, G.; Ballabio, C.; Ruggeri, R.; Fagnocchi, L.; Anderle, M.; Morassut, I.; Caron, D.; Garilli, F.; Gianno, F.; Giangaspero, F.; Piazza, S.; Romanel, A.; Zippo, A.; Tiberi, L.. - In: CELL REPORTS. - ISSN 2211-1247. - 29:12(2019), pp. 4036-4052. [10.1016/j.celrep.2019.11.046]

Truncated BRPF1 cooperates with smoothened to promote adult shh medulloblastoma

Gianno F.;Giangaspero F.;
2019

Abstract

The transition of neural progenitors to differentiated postmitotic neurons is mainly considered irreversible in physiological conditions. In the present work, we show that Shh pathway activation through SmoM2 expression promotes postmitotic neurons dedifferentiation, re-entering in the cell cycle and originating medulloblastoma in vivo. Notably, human adult patients present inactivating mutations of the chromatin reader BRPF1 that are associated with SMO mutations and absent in pediatric and adolescent patients. Here, we found that truncated BRPF1 protein, as found in human adult patients, is able to induce medulloblastoma in adult mice upon SmoM2 activation. Indeed, postmitotic neurons re-entered the cell cycle and proliferated as a result of chromatin remodeling of neurons by BRPF1. Our model of brain cancer explains the onset of a subset of human medulloblastoma in adult individuals where granule neuron progenitors are no longer present.
2019
adult; BRPF1; cell-of-origin; dedifferentiation; medulloblastoma; SHH; super-enhancers
01 Pubblicazione su rivista::01a Articolo in rivista
Truncated BRPF1 cooperates with smoothened to promote adult shh medulloblastoma / Aiello, G.; Ballabio, C.; Ruggeri, R.; Fagnocchi, L.; Anderle, M.; Morassut, I.; Caron, D.; Garilli, F.; Gianno, F.; Giangaspero, F.; Piazza, S.; Romanel, A.; Zippo, A.; Tiberi, L.. - In: CELL REPORTS. - ISSN 2211-1247. - 29:12(2019), pp. 4036-4052. [10.1016/j.celrep.2019.11.046]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1361000
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