Cortical neurons are born in strict order: subtypes born earliest form layer one and the subplate; consecutively later-born subtypes construct the six cortical layers from the bottom up. The researchers now show that vertebrate neural progenitors maintain this order without extrinsic cues. “In vitro recapitulation of normal timing suggests that there is an internal program,” says Shen.
The internal controller seems to be the Foxg1 transcription factor, which was previously linked to the control of timing in neurogenesis. When the researchers knocked down Foxg1, older progenitors reacquired their ability to make younger subtypes. The lab is now looking for changes in gene expression stemming from reduced Foxg1 levels. “If we can identify the genes controlling the timing process,” Shen notes, “we may be able to make or suppress a subtype by manipulating these genes.”
The findings also sound a note of caution for therapeutic stem cell research. Progenitors from younger mouse embryos could produce the full complement of subtypes, but older progenitors generated only later-born cells. “Stem cells may be limited in their ability to provide different neurons,” Shen says, “depending on the stage of extraction.”