Even in phosphate-buffered saline alone, ES cells rapidly acquire neural precursor markers, including Nestin (green).

Given a choice, embryonic stem (ES) cells prefer to join the neural lineage, according to findings on page 79. The results from Smukler et al. imply that other cell types arise only when the neural lineage is actively blocked.

Uncovering the default pathway for ES cells is tricky. The cells must be shielded from any signals that influence their development. Yet media devoid of instructive signals are not very supportive of cell survival. Smukler and colleagues indeed found that 75% of cells derived from mouse ES cells plated on serum-free media died within a day.

But by wading through this massive cell death, the group found that most of the cells that survived on media lacking all instructive cues rapidly acquired neural stem cell (NSC) characteristics. Even before their first mitosis, the ES cells expressed markers indicative of a cell type intermediate between ES cells and NSCs. The group calls these cells primitive NSCs, because they can still adopt some nonneural fates if given the right growth conditions. Primitive NSCs then produce definitive NSCs, which are committed to this state and can be passaged indefinitely.

Survival factors, including cAMP, did not change lineage choice, but did allow more of the ES cells to survive and thus become primitive NSCs. Blocking apoptotic pathways also improved NSC production. Once they became primitive NSCs, the cells produced their own survival factors—FGFs, which also increased proliferation.

Smukler imagines that the evolutionary emergence of the nervous system conferred an increased fitness. A strong selective pressure might therefore exist to ensure that neural tissue develops at all costs. The default nature of the neural stem cell fate helps guarantee that neural tissue production perseveres even if instructive cues are faulty or absent.

Although neural master regulatory genes have not yet been identified, the findings suggest that they would be repressed during early development, when other tissues are emerging. Only by relieving this inhibition would the nervous system develop. These functions might be performed in vivo by BMPs, which block neural fates, and by node-secreted factors, which antagonize BMPs and organize neural tissue formation.