Title:
Mouse Embryonic Stem Cell-Based Drug Screen for Novel Modulators of Cell Differentiation in Early Mammalian Embryogenesis

Hiroshi Nishina
Professor,
Department of Developmental and Degenerative Biology,
Medical Research Institute
Tokyo Medical and Dental Univerity

Abstract:
Many studies have shown that specific tissue culture conditions can direct the differentiation of murine embryonic stem (mES) cells into a variety of cell types, including cardiomyocytes and neurons. However, the molecular mechanisms that control lineage commitment decisions by ES cells are still poorly understood. We have performed an mES cell-based screen of 1,600 well-characterized compounds to identify cell signals involved in primitive streak formation, which induces cell differentiation in the gastrula stage. We discovered that antagonists specifically targeting muscarinic acetylcholine receptors (mAchRs) suppressed the expression of genes essential for primitive streak formation, including Wnt3, and thereby blocked mesodermal progenitor differentiation. We also found that statins, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors, induced a similar phenotype. Inhibition of HMGCR activity in zebrafish embryos also decreased mesodermal gene expression and increased ectodermal gene expression. Thus, our screen can reveal important new insights into the molecular mechanisms controlling early cell differentiation, including primitive streak formation.