FoxG1 is an evolutionarily conserved, winged-helix transcriptional repressor that maintains progenitor cells in the vertebrate forebrain. How the activity of FoxG1 is regulated is not known. Here, we report that in the developing Xenopus and mouse forebrain, FoxG1 is nuclear in progenitor cells but cytoplasmic in differentiating cells. The subcellular localisation of FoxG1 is regulated at the post-translational level by casein kinase I (CKI) and fibroblast growth factor (FGF) signalling. CKI phosphorylation of Ser 19 of FoxG1 promotes nuclear import, whereas FGF-induced phosphorylation of Thr 226 promotes nuclear export. Interestingly, FGF-induced phosphorylation of FoxG1 is mediated Akt kinase (also known as protein B kinase, PKB) kinase, rather than the MAPK pathway. Phosphorylation of endogenous FoxG1 is blocked by CKI and Akt inhibitors. In the mouse olfactory placode cell line OP27, and in cortical progenitors, increased FGF signalling causes FoxG1 to exit the nucleus and promotes neuronal differentiation, whereas FGF and Akt inhibitors block this effect. Thus, CKI and FGF signalling converge on an antagonistic regulation of FoxG1, which in turn controls neurogenesis in the forebrain.

Transforming growth factor-b (TGF-b) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-b are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no signi®cant functional redundancy between TGF-b1, -2 and -3. While signal transduction by TGF-b1 has been well characterized, receptor binding and activation by the TGF-b2 isoform is less well understood. Here, we show that TbRII-B, an alternatively spliced variant of the TGF-b type II receptor, is a TGF-b2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-b type III receptor (TbRIII). L6 cells lacking endogenous TbRIII as well as TbRII-B do not respond to TGF-b2. Transfection of these cells with TbRII-B restores TGF-b2 sensitivity. The expression of TbRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-b2 has a predominant role. This re¯ects the importance of this receptor in TGF-b isoform-speci®c signalling.