Calcineurin signaling regulates neural induction through antagonizing the BMP pathway.
Development of the nervous system begins with neural induction, which is controlled by complex signaling networks functioning in concert with one another. Fine-tuning of the bone morphogenetic protein (BMP) pathway is essential for neural induction in the developing embryo. However, the molecular mechanisms by which cells integrate the signaling pathways that contribute to neural induction have remained unclear. We find that neural induction is dependent on the Ca(2+)-activated phosphatase calcineurin (CaN). Fibroblast growth factor (FGF)-regulated Ca(2+) entry activates CaN, which directly and specifically dephosphorylates BMP-regulated Smad1/5 proteins. Genetic and biochemical analyses revealed that CaN adjusts the strength and transcriptional output of BMP signaling and that a reduction of CaN activity leads to an increase of Smad1/5-regulated transcription. As a result, FGF-activated CaN signaling opposes BMP signaling during gastrulation, thereby promoting neural induction and the development of anterior structures.
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
Ahryon
A
Cho
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
Yitai
Y
Tang
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Jonathan
J
Davila
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
Suhua
S
Deng
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
Lei
L
Chen
Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
Erik
E
Miller
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Marius
M
Wernig
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
Isabella A
IA
Graef
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000187:drug effects / Q000502:physiology; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000378:metabolism / Q000494:pharmacology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D016559:Tacrolimus / Q000494:pharmacology
D019485:Bone Morphogenetic Proteins; D007166:Immunosuppressive Agents; D005346:Fibroblast Growth Factors; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus