The neural progenitor-specifying activity of FoxG1 is antagonistically regulated by CKI and FGF.
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.
Regad
Tarik
T
The Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QR, UK.
Roth
Martin
M
Bredenkamp
Nicholas
N
Illing
Nicola
N
Papalopulu
Nancy
N
D000595:Amino Acid Sequence; D000818:Animals; D047389:Casein Kinase I / Q000378:metabolism*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction; D013912:Threonine; D014162:Transfection; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology
D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D029867:Xenopus Proteins; D016222:Fibroblast Growth Factor 2; D013912:Threonine; D012694:Serine; D047389:Casein Kinase I; D051057:Proto-Oncogene Proteins c-akt