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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE260851 | GEO | 2025/04/09

REPOSITORIES: GEO

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Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma

Project description:Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous germline Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the exclusivity of ELP1-associated MBs in SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved HDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.

2025-04-11 | PXD050488 | Pride

Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma

2025-04-11 | PXD050487 | Pride

Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [bulkRNA]

Project description:Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the exclusivity of ELP1-associated tumors in SHH-3. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.

2025-04-10 | GSE260623 | GEO

Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [DNA_methylation_array]

Project description:Mouse tumor methylation profiling by MouseMethylation Beadchips (MM285) platform

2025-04-09 | GSE260660 | GEO

Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma.

Project description:Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma.

| PRJNA1083708 | ENA

Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [DNA_methylation_array]

Project description:Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [DNA_methylation_array]

| PRJNA1082640 | ENA

Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [bulkRNA]

Project description:Germline ELP1 deficiency sensitizes cerebellar granule neuron progenitors to SHH medulloblastoma [bulkRNA]

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Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma.

Project description:Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MBSHH cases and that FGF5 expression is uniquely upregulated in infantile MBSHH tumors. Similarly, mice lacking SUFU (Sufu-cKO) ectopically express Fgf5 specifically along the secondary fissure where GNPs harbor preneoplastic lesions and show that FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MBSHH.

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Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells.

Project description:Precise regulation of neuroprogenitor cell proliferation and differentiation is required for successful brain development, but the factors that contribute to this are only incompletely understood. The transcription factor ATF5 promotes proliferation of cerebral cortical neuroprogenitor cells and its down regulation permits their differentiation. Here, we examine the expression and regulation of ATF5 in cerebellar granule neuron progenitor cells (CGNPs) as well as the role of ATF5 in the transition of CGNPs to postmitotic cerebellar granule neurons (GCNs). We find that ATF5 is expressed by proliferating CGNPs in both the embryonic and postnatal cerebellar external granule layer (EGL) and in the rhombic lip, the embryonic structure from which the EGL arises. In contrast, ATF5 is undetectable in postmitotic GCNs. In highly enriched dissociated cultures of CGNPs and CGNs, ATF5 is expressed only in CGNPs. Constitutive ATF5 expression in CGNPs does not affect their proliferation or exit from the cell cycle. In contrast, in presence of sonic hedgehog (Shh), a mitogen for CGNPs, constitutively expressed ATF5 promotes CGNP proliferation and delays their cell cycle exit and differentiation. Conversely, ATF5 loss-of-function conferred by a dominant-negative form of ATF5 significantly diminishes Shh-stimulated CGNP proliferation and promotes differentiation. In parallel with its stimulation of CGNP proliferation, Shh enhances ATF5 expression by what appeared to be a posttranscriptional mechanism involving protein stabilization. These findings indicate a reciprocal interaction between ATF5 and Shh in which Shh stimulates ATF5 expression and in which ATF5 contributes to Shh-stimulated CGNP expansion.

| S-EPMC3857133 | biostudies-literature

Norrin-dependent gene expression in murine cerebellar granule neuron progenitors and Patched medulloblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-10-12 | GSE81964 | GEO