A Simple and Scalable Zebrafish Model of Sonic Hedgehog Medulloblastoma

Abstract

SummaryMedulloblastoma (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 the first zebrafish model of SHH MB using CRISPR to mutateptch1, the primary genetic driver in human SHH MB. These tumors rapidly arise adjacent to the valvula cerebelli and resemble human SHH MB by histology and comparative genomics. In addition,ptch1-deficient MB tumors with loss oftp53have aggressive tumor histology and significantly worse survival outcomes, comparable to human patients. The simplicity and scalability of theptch1MB model makes it highly amenable to CRISPR-based genome editing screens to identify genes required for SHH MB tumor formationin vivo, and here we identify thegrk3kinase as one such target.