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miR-17∼92 簇家族在小脑和髓母细胞瘤发育中的作用。

Role of the miR-17∼92 cluster family in cerebellar and medulloblastoma development.

机构信息

Department of Tumor Cell Biology, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.

Department of Tumor Cell Biology, Danny Thomas Research Center, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA Present address: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.

出版信息

Biol Open. 2014 Jun 13;3(7):597-605. doi: 10.1242/bio.20146734.

DOI:10.1242/bio.20146734
PMID:24928431
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4154296/
Abstract

The miR-17∼92 cluster family is composed of three members encoding microRNAs that share seed sequences. To assess their role in cerebellar and medulloblastoma (MB) development, we deleted the miR-17∼92 cluster family in Nestin-positive neural progenitors and in mice heterozygous for the Sonic Hedgehog (SHH) receptor Patched 1 (Ptch1(+/-)). We show that mice in which we conditionally deleted the miR-17∼92 cluster (miR-17∼92(floxed/floxed); Nestin-Cre(+)) alone or together with the complete loss of the miR-106b∼25 cluster (miR-106b∼25(-/-)) were born alive but with small brains and reduced cerebellar foliation. Remarkably, deletion of the miR-17∼92 cluster abolished the development of SHH-MB in Ptch1(+/-) mice. Using an orthotopic transplant approach, we showed that granule neuron precursors (GNPs) purified from the cerebella of postnatal day 7 (P7) Ptch1(+/-); miR-106b∼25(-/-) mice and overexpressing Mycn induced MBs in the cortices of naïve recipient mice. In contrast, GNPs purified from the cerebella of P7 Ptch1(+/-); miR-17∼92(floxed/floxed); Nestin-Cre(+) animals and overexpressing Mycn failed to induce tumors in recipient animals. Taken together, our findings demonstrate that the miR-17∼92 cluster is dispensable for cerebellar development, but required for SHH-MB development.

摘要

miR-17∼92 簇家族由三个编码具有种子序列的 microRNA 的成员组成。为了评估它们在小脑和髓母细胞瘤（MB）发育中的作用，我们在巢蛋白阳性神经祖细胞中和 Sonic Hedgehog（SHH）受体 Patched 1（Ptch1(+/-)）杂合子的小鼠中删除了 miR-17∼92 簇家族。我们表明，在我们单独或与 miR-106b∼25 簇的完全缺失（miR-106b∼25(-/-)）一起条件性删除 miR-17∼92 簇（miR-17∼92(floxed/floxed); Nestin-Cre(+))的小鼠能够存活，但大脑较小，小脑褶皱减少。值得注意的是，删除 miR-17∼92 簇消除了 Ptch1(+/-)小鼠中的 SHH-MB 发育。通过原位移植方法，我们表明从出生后第 7 天（P7）Ptch1(+/-); miR-106b∼25(-/-)小鼠的小脑纯化的颗粒神经元前体细胞（GNPs）和过表达 Mycn 诱导了幼稚受体小鼠皮质中的 MB。相比之下，从出生后第 7 天（P7）Ptch1(+/-); miR-17∼92(floxed/floxed); Nestin-Cre(+)动物的小脑纯化的 GNPs 和过表达 Mycn 未能在受体动物中诱导肿瘤。总之，我们的研究结果表明，miR-17∼92 簇对于小脑发育不是必需的，但对于 SHH-MB 发育是必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/a16ec1c66d31/bio-03-07-597-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/1cb9546cf1cb/bio-03-07-597-f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/2e68177cb394/bio-03-07-597-f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/2723b3697f38/bio-03-07-597-f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/156b85e0b013/bio-03-07-597-f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/1792f2d0b49d/bio-03-07-597-f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/511dfc277389/bio-03-07-597-f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/fb36804cfc01/bio-03-07-597-f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/fc3319a98709/bio-03-07-597-f08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/c21a65e18fd0/bio-03-07-597-f09.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/a16ec1c66d31/bio-03-07-597-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/1cb9546cf1cb/bio-03-07-597-f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/2e68177cb394/bio-03-07-597-f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/2723b3697f38/bio-03-07-597-f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/156b85e0b013/bio-03-07-597-f04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/1792f2d0b49d/bio-03-07-597-f05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/511dfc277389/bio-03-07-597-f06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/fb36804cfc01/bio-03-07-597-f07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/fc3319a98709/bio-03-07-597-f08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/c21a65e18fd0/bio-03-07-597-f09.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ce3/4154296/a16ec1c66d31/bio-03-07-597-f10.jpg

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