Defining the crucial role of MAGOH in cerebellar development and the potential for targeting the EJC in medulloblastoma treatment

摘要 我们建议研究外显子连接复合体(EJC)在小脑发育和髓母细胞瘤中的作用。 髓母细胞瘤是儿童最常见的恶性脑肿瘤，发生于出生后。 小脑神经发生。我们发现，出生后小脑中的神经前体细胞严格要求EJC功能， 由于EJC成分的基因缺失，Magoh会导致灾难性的DNA损伤和细胞死亡，特别是在这些 细胞。我们开发了可以通过时间控制删除Magoh的小鼠，并发现Magoh的缺失导致 72小时内整个小脑神经前体细胞死亡。此外，我们提出了易患髓母细胞瘤的 通过时间控制可以删除Magoh的小鼠，并发现肿瘤中的Magoh缺失导致了DNA 损伤和细胞死亡与祖细胞的影响相似。基于这些发现，我们认为EJC扮演着一个 在维持小脑祖细胞的基因组完整性和生存方面发挥了以前未被认识到的核心作用 髓母细胞瘤细胞。揭示EJC调节祖细胞和髓母细胞瘤的机制 细胞将为小头症脑生长障碍的发病机制提供新的见解，并可能导致新的 髓母细胞瘤的治疗。赠款的目标1将重点放在小脑前体细胞上，并使用Magoh缺失来 确定依赖于EJC的DNA完整性和细胞存活的机制。Aim 2将使用Magoh删除来 在原发的髓母细胞瘤小鼠模型中，确定EJC干扰如何改变肿瘤的生长。这些目标 将展示在大脑发育过程中，EJC如何维持祖细胞的存活，并测试EJC可以 有针对性地提高髓母细胞瘤的治疗水平。

ABSTRACT We propose to study the role of the exon junction complex (EJC) in cerebellar development and medulloblastoma. Medulloblastoma is the most common malignant brain tumor in children, and it arises as a disruption of postnatal cerebellar neurogenesis. We have found that neural progenitors in the postnatal cerebellum strictly require EJC function, as genetic deletion of the EJC component Magoh induces catastrophic DNA damage and cell death specifically in these cells. We developed mice in which Magoh could be deleted with temporal control, and found that Magoh deletion causes cell death throughout the cerebellar progenitor population within 72 hours. Moreover, we raised medulloblastoma-prone mice in which Magoh could be deleted with temporal control and found the Magoh deletion in tumors caused DNA damage and cell death similar to the effect in progenitor cells. Based on these findings, we propose that the EJC plays a central, previously unappreciated role in maintaining the genomic integrity and the survival of cerebellar progenitors and medulloblastoma cells. Uncovering the mechanisms through which the EJC regulates progenitors and medulloblastoma cells will provide new insight into the pathogenesis of brain growth failure in microcephaly and may lead to new treatments for medulloblastoma. Aim 1 of the grant will focus on cerebellar progenitors and use Magoh deletion to identify the mechanisms of DNA integrity and cell survival that depend on the EJC. Aim 2 will use Magoh deletion to determine how EJC disruption alters tumor growth in a primary, in vivo mouse model of medulloblastoma. These Aims will show how the EJC maintains progenitor survival during brain growth and test the hypothesis that the EJC can be targeted to improve medulloblastoma therapy.