Fezf2 regulates telencephalic precursor differentiation from mouse embryonic stem cells.

The mechanisms by which transcription factors control stepwise lineage restriction during the specification of cortical neurons remain largely unknown. Here, we investigated the role of forebrain embryonic zinc finger like (Fezf2) in this process by generating Fezf2 knockdown and tetracycline-inducible Fezf2 overexpression mouse embryonic stem cell (mESC) lines. The overexpression of Fezf2 at early time points significantly increased the generation of rostral forebrain progenitors (Foxg1(+), Six3(+)) and inhibited the expression of transcription factors which are expressed by the midbrain and caudal diencephalon (En1(+), Irx(+)). This effect was partially achieved by the regulation of Wnt signaling during this critical early time window. The role of Fezf2 in regulating the rostrocaudal patterning was further confirmed by the significant decrease in the expression of Foxg1 and Six3 and the increase in the expression of En1 when Fezf2 was knocked down. In addition, Fezf2 overexpression at later time points had little effect on the expression of Foxg1 and Six3. Instead, Fezf2 promotes the generation of dorsal telencephalic progenitors and deep-layer cortical neurons at later stages. Collectively, our data suggest that Fezf2 controls the specification of telencephalic progenitors from mESCs through differentially regulating the expression of rostrocaudal and dorsoventral patterning genes.