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Embryonic stem cells assume a primitive neural stem cell fate in the absence of extrinsic influences
The mechanisms governing the emergence of the earliest mammalian neural cells during development remain incompletely characterized. A default mechanism has been suggested to underlie neural fate acquisition; however, an instructive process has also been proposed. We used mouse embryonic stem (ES) cells to explore the fundamental issue of how an uncommitted, pluripotent mammalian cell will self-organize in the absence of extrinsic signals and what cellular fate will result. To assess this default state, ES cells were placed in conditions that minimize external influences. Individual ES cells were found to rapidly transition directly into neural cells, a process shown to be independent of suggested instructive factors (e.g., fibroblast growth factors). Further, we provide evidence that the default neural identity is that of a primitive neural stem cell (NSC). The exiguous conditions used to reveal the default state were found to present primitive NSCs with a survival challenge (limiting their persistence and proliferation), which could be mitigated by survival factors or genetic interference with apoptosis.
S. Xu's present address is Dept. of Ophthalmology/Neurological Sciences, Rush University Medical Center, Chicago, IL 60612.
Abbreviations used in this paper: aif, apoptosis-inducing factor; apaf1, apoptotic protease activating factor 1; BMP, bone morphogenic protein; cas9, caspase 9; cGMP, cyclic guanosine monophosphate; E, embryonic day; EB, embryoid body; ES, embryonic stem; ICM, inner cell mass; LIF, leukemia inhibitory factor; NAC, N-acetyl-L-cysteine; NFM, neurofilament-M; NSC, neural stem cell; NS, neurosphere; pCPT, 8-(4-chlorophenylthio).
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