Combined single-cell and spatial transcriptomics reveal the precise cellular states of postnatal cerebellar granule cells and connection with medulloblastoma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE156633 | GEO | 2021/01/18
REPOSITORIES: GEO
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Project description:We performed gene-expression analysis of mouse cerebellar granule cell layer as compared to that of Purkinje cells. DNA microarray analysis detected genes in cerebellar granule cell layer, most of which are classified into functional molecule categories. Our comparative analysis between Purkinje cells and the granule cell layer showed that the characteristic expression pattern in Purkinje cells was particularly represented by M-bM-^@M-^\the neural communication systemM-bM-^@M-^] components. Pukinje cells and granule cell layer of the mouse cerebellum were collected by laser microdissection for RNA extraction and hybridization on Affymetrix microarrays.
2013-01-17 | E-GEOD-26750 | biostudies-arrayexpress
Project description:Origins of the brain tumor, medulloblastoma, from stem cells or restricted pro-genitor cells are unclear. To investigate this, we activated oncogenic Hedgehog signaling in multipotent and lineage-restricted CNS progenitors. We observed that normal unipo-tent cerebellar granule neuron precursors (CGNP) derive from hGFAP+ and Olig2+ rhombic lip progenitors. Hedgehog activation in a spectrum of early and late stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and that they retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hedgehog signaling promotes medulloblastoma from lineage-restricted granule cell progenitors. Gene expression profiling of cerebellar tumors generated from various early and late stage CNS progenitor cells. Experiment Overall Design: Group comparisons with biological replicates
2008-10-21 | E-GEOD-11859 | biostudies-arrayexpress
Project description:Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common malignant tumor of the central nervous system. About 20-30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened is a key transducer of the Shh pathway. Activating mutations in Smoothened that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the molecular and cellular effects of Smoothened variants in normal development and medulloblastoma genesis, we generated the SmoA2 transgenic mouse model which expresses the transgene exclusively in granule neuron precursors. In this study, we demonstrate how two point mutations in a single molecule can produce starkly different phenotypes as seen in comparison to our previous model, ND2:SmoA1. The SmoA2 mice have severe aberrations in cerebellar development whereas the SmoA1 mice are largely normal during development. Medulloblastomas in the SmoA2 mice develop in the dysplastic cerebellar milieu. Intriguingly, despite disruptions in the stereotypic organization of the cerebellum, the SmoA2 mice do not exhibit any overt abnormalities in motor coordination. The differences in the global transcriptional profiles downstream of SmoA1 and SmoA2 further demonstrate the distinctiveness of the two oncogenic Smoothened mutations. The SmoA2 model serves as a unique spatiotemporal tool to investigate the functional significance of the reiterative cerebellar circuitry as well as to further understand Shh pathway mechanics in cerebellar development and oncogenesis. We previously generated a SmoA1 transgenic mouse medulloblastoma model, which expresses the SmoA1 transgene driven by the GNP-specific fragment of the promoter of ND2 transcription factor leading to constitutively active Shh signaling exclusively in the cerebellum. In this study, we characterize the ND2:SmoA2 transgenic mouse model with a similarly designed transgene expressing the SmoA2 mutation. To assess transcriptional changes downstream of SmoA1 and SmoA2, we evaluated global gene expression profiles of P5 SmoA1, SmoA2 and Wt age-matched cerebella. We chose this specific developmental stage because (1) the phenotypes of SmoA1 and SmoA2 are robust and distinct at P5; (2) at P5 GNPs undergo proliferation, migration and differentiation and therefore expression profiling could capture key differences in multiple processes.
2012-11-02 | E-GEOD-34593 | biostudies-arrayexpress
Project description:Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common malignant tumor of the central nervous system. About 20-30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened is a key transducer of the Shh pathway. Activating mutations in Smoothened that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the molecular and cellular effects of Smoothened variants in normal development and medulloblastoma genesis, we generated the SmoA2 transgenic mouse model which expresses the transgene exclusively in granule neuron precursors. In this study, we demonstrate how two point mutations in a single molecule can produce starkly different phenotypes as seen in comparison to our previous model, ND2:SmoA1. The SmoA2 mice have severe aberrations in cerebellar development whereas the SmoA1 mice are largely normal during development. Medulloblastomas in the SmoA2 mice develop in the dysplastic cerebellar milieu. Intriguingly, despite disruptions in the stereotypic organization of the cerebellum, the SmoA2 mice do not exhibit any overt abnormalities in motor coordination. The differences in the global transcriptional profiles downstream of SmoA1 and SmoA2 further demonstrate the distinctiveness of the two oncogenic Smoothened mutations. The SmoA2 model serves as a unique spatiotemporal tool to investigate the functional significance of the reiterative cerebellar circuitry as well as to further understand Shh pathway mechanics in cerebellar development and oncogenesis.
2012-11-02 | GSE34593 | GEO
Project description:Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic Hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide novel insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases. We used microarrays to detail the global programme of gene expression underlying the knockout of Crebbp in murine granule neuron precursors, chronically induced at embryonic stages of development.
2017-11-22 | GSE107252 | GEO
Project description:Origins of the brain tumor, medulloblastoma, from stem cells or restricted pro-genitor cells are unclear. To investigate this, we activated oncogenic Hedgehog signaling in multipotent and lineage-restricted CNS progenitors. We observed that normal unipo-tent cerebellar granule neuron precursors (CGNP) derive from hGFAP+ and Olig2+ rhombic lip progenitors. Hedgehog activation in a spectrum of early and late stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and that they retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hedgehog signaling promotes medulloblastoma from lineage-restricted granule cell progenitors. Gene expression profiling of cerebellar tumors generated from various early and late stage CNS progenitor cells.
2008-06-24 | GSE11859 | GEO
Project description:We performed gene-expression analysis of mouse cerebellar granule cell layer as compared to that of Purkinje cells. DNA microarray analysis detected genes in cerebellar granule cell layer, most of which are classified into functional molecule categories. Our comparative analysis between Purkinje cells and the granule cell layer showed that the characteristic expression pattern in Purkinje cells was particularly represented by “the neural communication system” components.
2013-01-17 | GSE26750 | GEO
Project description:Combined single-cell and spatial transcriptomics reveal the precise cellular states of postnatal cerebellar granule cells and connection with medulloblastoma
| PRJNA658557 | ENA
Project description:Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype), arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer. A total of 16 samples are analyzed, repsresenting 4 experimental groups: Ctnnb1 medulloblastoma (3 samples); Ptch1 medulloblastoma (6 samples); embryonic dorsal brainstem (4 samples); and postnatal granule neuron precursor cells (3 samples). Every sample was prepared from a different mouse.
2010-11-01 | E-GEOD-24628 | biostudies-arrayexpress
Project description:Homeobox gene Tlx3 is known to promote glutamatergic differentiation and is expressed in post-mitotic neurons of CNS. Contrary to this here, we discovered that Tlx3 is expressed in the proliferating progenitors of the external granule layer in the cerebellum, and examined factors that regulate this expression. Using Pax6-/-Sey mouse model and molecular interaction studies we demonstrate Pax6 is a key activator of Tlx3 specifically in cerebellum, and induces its expression starting at embryonic day (E)15. By Postnatal day (PN)7, Tlx3 is expressed in a highly restricted manner in the cerebellar granule neurons of the posterior cerebellar lobes, where it is required for the restricted expression of nicotinic cholinergic receptor-α3 subunit (Chrnα3) and other genes involved in formation of synaptic connections and neuronal migration. These results demonstrate a novel role for Tlx3 and indicate that Pax6-Tlx3 expression and interaction is part of a region specific regulatory network in cerebellum and its deregulation during development could possibly lead to Autistic spectral disorders (ASD) Anterior and posterior lobes of PN7 mouse cerebellum were isolated separately and differentially expressed genes were identified.
2016-06-30 | E-GEOD-82097 | biostudies-arrayexpress