Speaker: Maura McGrail, Iowa State University genetics, development and cell biology associate professor

Title: "Zebrafish Cre/lox conditional genetics to investigate epigenetic mechanisms in brain development and disease"

Abstract: Zebrafish is one of the premier vertebrate genetic model systems for human health and is increasingly used for post-embryonic and adult models of disease and tissue regeneration. Despite its prominent role, zebrafish has been limited by a lack of genetic tools to model lineage specific gene function with conditional gene inactivation. To address this critical need, we have innovated genome editing strategies to generate zebrafish Cre/lox regulated conditional alleles using CRISPR/Cas9 precision targeted integration. In this talk I will highlight two projects that illustrate how we are using cell lineage specific conditional gene models to investigate fundamental epigenetic mechanisms driving brain development and oncogenesis. Double conditional knockout of Rb and the epigenetic regulator Hdac1 in forebrain neural progenitors reveals that a loss of Hdac1 suppresses the Rb proliferation defect, suggesting Hdac1 function counteracts Rb driven cell cycle exit. These results lead to testable hypotheses on the role of Hdac1 in integrating growth signals with Rb cell cycle control through epigenetic regulation of cell cycle and Shh target gene expression. Using this conditional knockout approach, we generated a new model of rare pediatric brain cancer. Beginning at 6 months of age adult fish with neural progenitor specific knockout of Rb developed poorly differentiated brain tumors. The tumors express a molecular signature similar to olig2+/sox10+ human CNS primitive neuroectodermal tumor subtype and elevated levels of chromatin remodelers including Hdac1. This model allows the possibility to profile the epigenetic time course of cellular transformation and gain new insight into the molecular mechanisms driving oncogenesis. Our conditional genetics strategies can be used to reveal novel genetic interactions and insight into mechanisms driving development and disease that can be widely applied in zebrafish.

Host: Yanhai Yin, genetics, development and cell biology chair