The neocortical progenitor specification program is established throughcombined modulation of SHH and FGF signaling

Neuronal progenitors in the developing forebrain undergo dynamic competence states to ensure timely generation of specific excitatory and inhibitory neuronal subtypes from distinct neurogenic niches of the dorsal and ventral forebrain, respectively. Here we show evidence of progenitor plasticity when Sonic hedgehog (SHH) signaling is left unmodulated in the embryonic neocortex of the dorsal forebrain. At early stages of corticogenesis, loss of Suppressor of Fused (Sufu), a potent inhibitor of SHH signaling, in neocortical progenitors, altered their transcriptomic landscape. Ectopic activation of SHH signaling occurred, via degradation of Gli3R, resulting in significant upregulation of Fibroblast Growth Factor 15 (FGF15) gene expression. Consequently, activation of FGF signaling, and its downstream effector the MAPK signaling, facilitated expression of genes characteristic of ventral forebrain progenitors. Our studies identify the importance of modulating extrinsic niche signals such as SHH and FGF15 to maintain the competency and specification program of neocortical progenitors throughout corticogenesis. SIGNIFICANCE STATEMENTLow levels of FGF15 control progenitor proliferation and differentiation during neocortical development but little is known on how FGF15 expression is maintained. Our studies identified SHH signaling as a critical activator of FGF15 expression during corticogenesis. We found that Sufu, via Gli3R, ensured low levels of FGF15 was expressed to prevent abnormal specification of neocortical progenitors. These studies advance our knowledge on the molecular mechanisms guiding the generation of specific neocortical neuronal lineages, their implications in neurodevelopmental diseases, and may guide future studies on how progenitor cells may be utilized for brain repair.