Wnt regulation of progenitor maturation in the cortex depends on Shh or fibroblast growth factor 2

In the embryonic mouse cerebral cortex, progenitors in the ventricular zone (VZ) undergo a developmental change between embryonic day 13 (E13) and E15. This results in the generation of a secondary proliferative population and the appearance of a second germinal layer, the subventricular zone (SVZ). We have shown previously that bone morphogenetic proteins (BMPs) and Fibroblast Growth Factor 2 (FGF2) act antagonistically to regulate the development of a subset of SVZ progenitors that normally express a high level of epidermal growth factor (EGF) receptors and divide in response to EGF. In the present study, we show that Wnt 7a, Wnt 7b, and Sonic Hedgehog (Shh) promote progenitor maturation in explant cultures, as reported for FGF2. Wnts 7a and 7b also stimulate the proliferation of neurogenic progenitors and increase the number of cells that can generate primary neurospheres. To determine whether Wnts, FGF2, and Shh act independently or in a common pathway, each factor was inhibited in cortical explants. This revealed that endogenous Wnts, FGF2, and Shh normally contribute to progenitor maturation. Moreover, Wnt 7a depends on FGF2 or Shh to promote maturation but not proliferation. Maturation induced by blocking BMPs also depends on Shh. In contrast, FGF2 promotes maturation by a Shh-independent mechanism. In vivo, progenitors infected with a Wnt 7a retrovirus at E10.5 were found preferentially in the SVZ at E16.5. These findings suggest that Wnts depend on Shh or FGF2 to promote progenitor maturation to an SVZ state in the embryonic cortex.