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Comprehensive analysis of microRNA expression in regionalized human neural progenitor cells reveals microRNA-10 as a caudalizing factor

ABSTRACT: MicroRNAs (miRNAs) have been implicated in regulating multiple processes during brain development in various species. However, the function of miRNAs in human brain development remains largely unexplored. Here, we provide a comprehensive analysis of miRNA expression of regionalized neural progenitor cells derived from human embryonic stem cells and human fetal brain. We found mir-92b-3p and mir-130b-5p to be specifically associated with neural progenitors and several miRNAs that display both age-specific and region-specific expression patterns. Among these miRNAs, we identified miR-10 to be specifically expressed in the human hindbrain and spinal cord, while absent from rostral regions. We found that miR-10 regulates a large number of genes enriched for functions including transcription, actin cytoskeleton and ephrin receptor signaling. When overexpressed, miR-10 influences caudalization of human neural progenitors cells. Together, these data confirms a role for miRNAs in establishing different human neural progenitor populations. This data set also provides a comprehensive resource for future studies investigating the functional role of different miRNAs in human brain development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71204 | GEO | 2015/10/26

SECONDARY ACCESSION(S): PRJNA290580

REPOSITORIES: GEO

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Project description:Medulloblastomas (MBs) are the most common brain tumors in children. Some are thought to originate from cerebellar granule neuron progenitors (GNPs) that fail to undergo normal cell cycle exit and differentiation. Since microRNAs regulate numerous aspects of cellular physiology and development, we reasoned that alterations in miRNA expression might contribute to MB. We tested this hypothesis using two spontaneous mouse MB models with specific initiating mutations, Ink4c-/-; Ptch1+/- and Ink4c-/-; p53-/-. We found that 26 miRNAs showed increased expression and 24 miRNAs showed decreased expression in proliferating mouse GNPs and MBs relative to mature mouse cerebellum, regardless of genotype. Among the 26 overexpressed miRNAs, nine were encoded by the miR-17~92 cluster family, a group of microRNAs implicated as oncogenes in several tumor types. Analysis of human MBs demonstrated that three miR-17~92 cluster miRNAs (miR-92, miR-19a and miR-20) were also overexpressed in human MBs with a constitutively activated SHH signaling pathway, but not in other forms of the disease. To test whether the miR-17~92 cluster could promote MB formation, we enforced expression of these miRNAs in GNPs isolated from cerebella of postnatal (P) day P6 Ink4c-/-; Ptch1+/- mice. These, but not similarly engineered cells from Ink4c-/-; p53-/- mice, formed MBs in orthotopic transplants with complete penetrance. Interestingly, orthotopic mouse tumors ectopically expressing miR-17~92 lost expression of the wild-type Ptch1 allele. Our findings suggest a functional collaboration between the miR-17~92 cluster and the SHH signaling pathway in the development of MBs in mouse and man. Samples: purified CGNP-like mouse medulloblastoma cells; purified CGNPs from age day 6 (P6) mice; whole cerebellum from P6 mice; whole cerebellum from 1 month old mice. Each from three backgrounds (except tumors) - wt; Ptc+/-,Ink4c-/-; p53-/-,Ink4c-/-. Two to five biological replicates each.

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Comprehensive analysis of microRNA expression in regionalized human neural progenitor cells reveals microRNA-10 as a caudalizing factor

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