HGG-27. Understanding the role of PLAG family transcription factors in cortex development and tumorigenesis

Abstract

Gliomas are the most common type of central nervous system (CNS) tumors in children. Therapy and outcome often reflect the grade of the tumor, with high grade glioma (HGG) leading to a significantly worse survival prognosis than low grade glioma. However, HGG are highly diverse regarding their molecular entities and clinical associations. In some pediatric-type histone 3 K27M mutated HGG, the zinc-finger transcription factor PLAG1 was previously found to be overexpressed, which is also confirmed by patient data from the INFORM program. Further, in a novel type of embryonic CNS tumors without histone mutations, the PLAG1-related genes PLAGL1/PLAGL2 are amplified. However, the consequences of aberrant PLAG gene expression on CNS tumor formation during development are unknown. Especially the understanding of downstream signaling pathways that are commonly altered by this transcription factor family could provide necessary starting points for more specific therapy. We use transgenic mouse models with targeted PLAG1 overexpression in neural stem and progenitor cells to investigate the function of PLAG1 in cerebral cortex development and tumorigenesis. We found that PLAG1 overexpression together with heterozygous loss of p53 activity causes neurological defects and impaired cortex development. Next, to understand how PLAG gene overexpression affects neural specification, we will overexpress the PLAG genes in embryonic neural stem and progenitor cells using in utero electroporation. After FACS isolation of electroporated cells and single nucleus RNA sequencing, we will assess how the overexpression changes the transcriptional trajectories of neural development in mouse cortex stem and progenitor cells. We hypothesize that an early event leads to the constitutive upregulation of PLAG genes, which are usually tightly regulated during development, in patients with pediatric brain tumors harboring aberrant PLAG gene expression. Deciphering the transcriptional downstream pathways of this aberrant expression in neural stem and progenitor cells seems promising to find new potential therapeutic targets.