Abstract：
Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ∼30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe a zebrafish model of SHH MB using CRISPR to create mutant ptch1, the primary genetic driver of human SHH MB. In these animals, tumors rapidly arise in the cerebellum and resemble human SHH MB by histology and comparative onco-genomics. Similar to human patients, MB tumors with loss of both ptch1 and tp53 have aggressive tumor histology and significantly worse survival outcomes. The simplicity and scalability of the ptch1-crispant MB model makes it highly amenable to CRISPR-based genome-editing screens to identify genes required for SHH MB tumor formation in vivo, and here we identify the gene encoding Grk3 kinase as one such target.
摘要：
髓母细胞瘤（MB）是儿童最常见的恶性脑肿瘤，分为三个主要亚组。Sonichedgehog（SHH）亚组占所有MB病例的30％，并且根据TP53状态具有显着的生存差异。这里,我们描述了一个SHHMB的斑马鱼模型，使用CRISPR创建突变ptch1，人类SHHMB的主要遗传驱动因子。在这些动物中，肿瘤在小脑中迅速出现，并通过组织学和比较细胞基因组学与人类SHHMB相似。类似于人类患者，ptch1和tp53缺失的MB肿瘤具有侵袭性肿瘤组织学和显著较差的生存结果。ptch1-crispantMB模型的简单性和可扩展性使其高度适合于基于CRISPR的基因组编辑筛选，以识别体内SHHMB肿瘤形成所需的基因。在这里，我们确定了编码Grk3激酶的基因作为一个这样的靶标。
