Quiescence is essential for long-term maintenance of adult stem cells. Niche signals regulate the transit of stem cells from dormant to activated states. Here we show that the E3-ubiquitin ligase Huwe1 (HECT, UBA and WWE domain containing 1) is required for proliferating stem cells of the adult mouse hippocampus to return to quiescence. Huwe1 destabilises pro-activation protein Ascl1 (achaete-scute family bHLH transcription factor 1) in proliferating hippocampal stem cells, which prevents accumulation of cyclin Ds and promotes the return to a resting state. When stem cells fail to return to quiescence, the proliferative stem cell pool becomes depleted. Thus, longterm maintenance of hippocampal neurogenesis depends on the return of stem cells to a transient quiescent state through the rapid degradation of a key activation factor.Stem cells contribute to tissue homeostasis by generating new differentiated cells. Adult stem cells can enter a reversible state of quiescence that protects the cells from damage and the population from depletion. Niche signals determine the balance between quiescent and activated states. Excessive quiescence leads to too few differentiated progeny whereas excessive proliferation exhausts the stem cell population (1).Neural stem cells (NSCs) in the dentate gyrus (DG) of the mouse hippocampus generate new granule neurons that integrate into the hippocampal circuit to modulate mood and memory (2, 3). Niche signals control expression of the transcription factor Ascl1 (achaete-scute family bHLH transcription factor 1), which in turn directs NSC proliferation (4). To identify factors that regulate Ascl1, we characterized proteins that co-immunoprecipitate with Ascl1 in cultured murine NSCs using mass spectrometry. We found that Huwe1 (HECT, UBA and WWE domain containing 1), a HECT domain E3 ubiquitin ligase associated with idiopathic intellectual disability and schizophrenia (5, 6), interacts with Ascl1 (Fig. S1). We generated embryonic telencephalon-and adult hippocampus-derived NSCs in which Huwe1 is
Recurrent genetic alterations in human medulloblastoma (MB) include mutations in the sonic hedgehog (SHH)signaling pathway and TP53 inactivation (∼25% and 10% of cases, respectively). However, mouse models of MB, regardless of their initiating lesions, generally depend upon p53 inactivation for rapid onset and high penetrance. The gene encoding the cyclin-dependent kinase inhibitor p18 Ink4c is transiently expressed in mouse cerebellar granule neuronal precursor cells (GNPs) as they exit the cell division cycle and differentiate. Coinactivation of Ink4c and p53 provided cultured GNPs with an additive proliferative advantage, either in the presence or absence of Shh, and induced MB with low penetrance but with greatly increased incidence following postnatal irradiation. In contrast, mice lacking one or two functional Ink4c alleles and one copy of Patched (Ptc1) encoding the Shh receptor rapidly developed MBs that retained wild-type p53. In tumor cells purified from double heterozygotes, the wild-type Ptc1 allele, but not Ink4c, was inactivated. Therefore, when combined with Ptc1 mutation, Ink4c is haploinsufficient for tumor suppression. Methylation of INK4C (CDKN2C) was observed in four of 23 human MBs, and p18 INK4C protein expression was extinguished in 14 of 73 cases. Hence, p18 INK4C loss may contribute to MB formation in children.[Keywords: Cyclin-dependent kinase inhibitors; haploinsufficiency; sonic hedgehog signaling] Supplemental material is available at http://www.genesdev.org. Neuronal proliferation, differentiation, and migration are coordinated during cerebellar development, and disruption of these processes can lead to medulloblastoma (MB), the most common malignant pediatric brain tumor (Gilbertson 2004;Marino 2005). Unlike most organogenesis, the cerebellum is largely formed after birth. In the newborn mouse (postnatal day 0 [P0]), the cerebellum is only composed of a thin layer of granule neuronal precursor cells (GNPs) overlying the Purkinje cell plate. Purkinje neurons produce the mitogen sonic hedgehog (Shh) that drives a massive proliferation of GNPs between P1 and P15, thereby expanding the external germinal layer (EGL). GNPs then exit the cell division cycle, extend axons, and migrate inward through the underlying Purkinje layer to form the more deeply situated internal granule layer (IGL). Differentiation of granule neurons results in the elaboration of parallel fibers within the external molecular layer of the cerebellum and the formation of synapses on the dendritic arbors of Purkinje cells (Goldowitz and Hamre 1998;Wang and Zoghbi 2001;Hatten 2002).Recurrent genetic alterations in childhood MBs include lesions in components of the SHH and WNT signaling pathways, persistent expression of pro-proliferative cell cycle control genes such as MYCN, cyclin D1, and cyclin D2 (CCND1 and CCND2, respectively), and inactivation of the TP53 tumor suppressor (Gilbertson 2004;Marino 2005). While these molecular alterations might account for the development of certain subgroups of human MB, the geneti...
The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.
Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein coding genes, and are rare in most pediatric cancers 1-3. We report highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs (snRNAs) in ~50% of Sonic Hedgehog medulloblastomas (Shh-MB), which were not present across other medulloblastoma subgroups. This U1-snRNA hotspot mutation (r.3a>g), was identified in <0.1% of 2,442 cancers across 36 other tumor types. Largely absent from infant Shh-MB, the mutation occurs in 97% of adults (Shhδ), and 25% of adolescents (Shhα). The U1-snRNA mutation occurs in the 5′ splice site binding region, and snRNA mutant tumors have significantly disrupted RNA splicing with an excess of 5′ cryptic splicing events. Mutant U1-snRNA mediated alternative splicing inactivates tumor suppressor genes (PTCH1), and activates oncogenes (GLI2, CCND2), represents a novel target for therapy, and constitutes a highly recurrent and tissue-specific mutation of a non-protein coding gene in cancer. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Signaling networks controlled by Sonic hedgehog (SHH) and the transcription factor Atoh1 regulate the proliferation and differentiation of cerebellar granule neuron progenitors (GNPs). Deregulations in those developmental processes lead to medulloblastoma formation, the most common malignant brain tumor in childhood. Although the protein Atoh1 is a key factor during both cerebellar development and medulloblastoma formation, up-to-date detailed mechanisms underlying its function and regulation have remained poorly understood. Here, we report that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1. Our results reveal that SHH and Atoh1 contribute to a positive autoregulatory loop promoting neuronal precursor expansion. Consequently, Huwe1 loss in mouse SHH medulloblastoma illustrates the disruption of this developmental mechanism in cancer. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in medulloblastoma.
Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses 1,2 and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients 3 . Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MB SHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MB SHH . Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHα subtype 4 and were characterized by universal biallelic inactivation of ELP1 due
Highlights d Atoh1 controls the presence of primary cilia in cerebellar granule neuron progenitors d Atoh1 requires the primary cilium to maintain the pool of proliferating progenitors d Atoh1 controls ciliogenesis by shaping centriolar satellites via its target Cep131
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