Context-dependent neuronal differentiation and germ layer induction of Smad4 −/− and Cripto −/− embryonic stem cells

• Published in: Molecular and cellular neuroscience Vol. 28; no. 3; pp. 417 - 429
• Main Authors: Sonntag, Kai-Christian, Simantov, Rabi, Björklund, Lars, Cooper, Oliver, Pruszak, Jan, Kowalke, Florian, Gilmartin, Jocelyn, Ding, Jixiang, Hu, Ya-Ping, Shen, Michael M., Isacson, Ole
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2005
• Subjects: Animals; Brain - cytology; Brain - embryology; Brain - metabolism; Cell Differentiation - physiology; Cell Lineage - physiology; DNA-Binding Proteins - genetics; Dopamine - metabolism; Ectoderm - cytology; Ectoderm - metabolism; Embryonic Induction - physiology; Epidermal Growth Factor - genetics; Germ Layers - cytology; Germ Layers - metabolism; Membrane Glycoproteins - genetics; Mesoderm - cytology; Mesoderm - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Proteins - genetics; Neurons - cytology; Neurons - metabolism; Phenotype; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Serotonin - metabolism; Signal Transduction - physiology; Smad4 Protein; Stem Cell Transplantation - methods; Trans-Activators - genetics; Transforming Growth Factor beta - metabolism
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2004.06.003

Activation of transforming growth factor-β (TGF-β) receptors typically elicits mesodermal development, whereas inhibition of this pathway induces neural fates. In vitro differentiated mouse embryonic stem (ES) cells with deletion of the TGF-β pathway-related factors Smad4 or Cripto exhibited increased numbers of neurons. Cripto −/− ES cells developed into neuroecto-/epidermal cell types, while Smad4 −/− cells also displayed mesodermal differentiation. ES cell differentiation into catecholaminergic neurons showed that these ES cells retained their ability to develop into dopaminergic and serotonergic neurons with typical expression patterns of midbrain and hindbrain genes. In vivo, transplanted ES cells to the mouse striatum became small neuronal grafts, or large grafts with cell types from all germ layers independent of their ES cell genotype. This demonstrates that Smad4 −/− and Cripto −/− ES cells favor a neural fate in vitro, but also express the mesodermal phenotype, implying that deletion of either Smad4 or Cripto is not sufficient to block nonneuronal tissue formation.