title: Context-dependent neuronal differentiation and germ layer induction of Smad4-/- and Cripto-/- embryonic stem cells.
abstract: Activation of transforming growth factor-beta (TGF-beta) 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-beta 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.
authors.affiliation: Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
authors.forename: Kai-Christian
authors.initials: KC
authors.lastname: Sonntag
authors.forename: Rabi
authors.initials: R
authors.lastname: Simantov
authors.forename: Lars
authors.initials: L
authors.lastname: Björklund
authors.forename: Oliver
authors.initials: O
authors.lastname: Cooper
authors.forename: Jan
authors.initials: J
authors.lastname: Pruszak
authors.forename: Florian
authors.initials: F
authors.lastname: Kowalke
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Gilmartin
authors.forename: Jixiang
authors.initials: J
authors.lastname: Ding
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Hu
authors.forename: Michael M
authors.initials: MM
authors.lastname: Shen
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism; D004475:Ectoderm / Q000166:cytology / Q000378:metabolism; D004627:Embryonic Induction / Q000502:physiology; D004815:Epidermal Growth Factor / Q000235:genetics*; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051901:Smad4 Protein; D033581:Stem Cell Transplantation / Q000379:methods; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C489450:Tdgf1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D012701:Serotonin; D004815:Epidermal Growth Factor; D004298:Dopamine