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Transcriptomic characterization of a mixed population of pluripotent stem cell derived cerebellar neuron-like progenitors

ABSTRACT: We set out to ascertain whether it was possible to use PSCs (pluripotent stem cells) to generate a mix of neuronal cell types resembling those in the cerebellum, most notably Purkinje and granule cells. Several groups have previously demonstrated generation of cerebellar-like neuronal cells from murine ESCs (embryonic stem cells), and more recently the Erceg group achieved similar success using human PSCs. Using principles from these studies we successfully induced expression of mid–hindbrain markers EN1 & GBX2 and later MATH1 (a transcription factor which marks rhombic lip/granule cell progenitors) in a mixed neuronal population derived from hPSCs. Further, we show that it is possible to expand these progenitors to produce spontaneously active neuronal cells with morphological similarities to neuronal cells at specific stages of cerebellar development. Based on morphology, electrophysiology, immunohistochemistry and transcriptomic analysis we demonstrate that these cells express behavior, markers and molecular signatures consistent with distinct epochs of cerebellar development spanning from the late embryonic to early postnatal periods. This study describes an in vitro model that provides insight into the early events that drive the formation of the human cerebellum with support from a high-resolution survey of the trancriptomic landscape, including expression of non-coding RNAs and specific transcript isoforms. The generated datasets and accompanying characterization are a valuable resource for researchers to formulate and test hypotheses regarding the molecular players that are involved in the formation of the cerebellum

ORGANISM(S): Homo sapiens

PROVIDER: GSE65423 | GEO | 2020/04/03

REPOSITORIES: GEO

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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.

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Transcriptomic characterization of a mixed population of pluripotent stem cell derived cerebellar neuron-like progenitors

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