Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in childhood. According to the World Health Organization (WHO) classification of central nervous system (CNS) tumors, this embryonal tumor is divided into a wingless (WNT)-activated, Sonic hedgehog (SHH)-activated, and non-WNT/non-SHH entity. The latter is poorly defined but frequently carries mutations in Brahma-related gene 1 (BRG1) or amplifications of MYCN. Here, we investigated whether a combination of a Brg1 knockout and an overexpression of MYCN in cerebellar granule neuron precursors or multipotent neural stem cells is sufficient to drive brain tumor formation in mice. To this end, we generated Math1-creERT2::Brg1fl/fl::lslMYCN and hGFAP-cre::Brg1fl/fl::lslMYCN mice, respectively. We did not observe brain tumor formation in any of these models. hGFAP-cre::Brg1fl/fl::lslMYCN mice revealed severe CNS abnormalities with short survival, similar to the situation with a sole loss of Brg1, as we previously described. Investigation of Math1-creERT2::Brg1fl/fl::lslMYCN mice with a tamoxifen induction at postnatal day 3 revealed a regular survival but significant increase in cerebellar granule neuron precursor proliferation, followed by a delayed inward migration of these cells. This is in stark contrast to the hypoplastic cerebellum that we previously observed after embryonic deletion of Brg1 in Math1 positive cerebellar granule neurons. Our results indicate a time-specific function of Brg1 in cerebellar granule neuron precursors. Yet, the exact temporal and spatial origin of non-WNT/non-SHH MB remains unclear.
Highlights
Medulloblastoma (MB) is the most common malignant brain tumor in children [1]
We further investigated the extent of Brg1 loss and MYCN overexpression by IHC
In controls and in Math1-creERT2::Brg1fl/ fl::lslMYCNfl/fl (Mert)::Bfl/wt animals, all cells were positive for Brg1 and MYCN was expressed in the outer external granular layer (EGL) (Fig. 1c, d, j, k)
Summary
Medulloblastoma (MB) is the most common malignant brain tumor in children [1]. This embryonal tumor arises in the posterior fossa and can be divided into at least three molecular subgroups: wingless (WNT)-activated MB, Sonic hedgehogDörthe Holdhof and Ji Hoon On contributed to this work.(SHH)-activated MB, and non-WNT/non-SHH MB [2]. Medulloblastoma (MB) is the most common malignant brain tumor in children [1] This embryonal tumor arises in the posterior fossa and can be divided into at least three molecular subgroups: wingless (WNT)-activated MB, Sonic hedgehog. BRG1 encodes one of the two mutually exclusive ATPase subunits of the SWItch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex, which regulates gene expression by increasing nucleosome mobility [7,8,9] It has been described as a tumor suppressor in different cancer entities, such as rhabdoid tumors, small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and lung cancer [10,11,12,13,14].
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