Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism.
Little is known about how neural stem cells are formed initially during development. We investigated whether a default mechanism of neural specification could regulate acquisition of neural stem cell identity directly from embryonic stem (ES) cells. ES cells cultured in defined, low-density conditions readily acquire a neural identity. We characterize a novel primitive neural stem cell as a component of neural lineage specification that is negatively regulated by TGFbeta-related signaling. Primitive neural stem cells have distinct growth factor requirements, express neural precursor markers, generate neurons and glia in vitro, and have neural and non-neural lineage potential in vivo. These results are consistent with a default mechanism for neural fate specification and support a model whereby definitive neural stem cell formation is preceded by a primitive neural stem cell stage during neural lineage commitment.
Tropepe
V
V
Department of Anatomy & Cell Biology, University of Toronto, Ontario M5S 1A8, Toronto, Canada.
Hitoshi
S
S
Sirard
C
C
Mak
T W
TW
Rossant
J
J
van der Kooy
D
D
D000818:Animals; D019521:Body Patterning / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology*; D048429:Cell Size / Q000235:genetics; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002678:Chimera / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000172:deficiency; D015850:Interleukin-6; D007381:Intermediate Filament Proteins / Q000187:drug effects / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008322:Mammals / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins; D009420:Nervous System / Q000166:cytology / Q000196:embryology* / Q000254:growth & development*; D064231:Nestin; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051901:Smad4 Protein; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D006133:Growth Substances; D015850:Interleukin-6; D007381:Intermediate Filament Proteins; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta