MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity.
We have investigated the genetic circuitry underlying the determination of neuronal identity, using mammalian peripheral autonomic neurons as a model system. Previously, we showed that treatment of neural crest stem cells (NCSCs) with bone morphogenetic protein-2 (BMP-2) leads to an induction of MASH1 expression and consequent autonomic neuronal differentiation. We now show that BMP2 also induces expression of the paired homeodomain transcription factor Phox2a, and the GDNF/NTN signalling receptor tyrosine kinase c-RET. Constitutive expression of MASH1 in NCSCs from a retroviral vector, in the absence of exogenous BMP2, induces expression of both Phox2a and c-RET in a large fraction of infected colonies, and also promotes morphological neuronal differentiation and expression of pan-neuronal markers. In vivo, expression of Phox2a in autonomic ganglia is strongly reduced in Mash1 -/- embryos. These loss- and gain-of-function data suggest that MASH1 positively regulates expression of Phox2a, either directly or indirectly. Constitutive expression of Phox2a, by contrast to MASH1, fails to induce expression of neuronal markers or a neuronal morphology, but does induce expression of c-RET. These data suggest that MASH1 couples expression of pan-neuronal and subtype-specific components of autonomic neuronal identity, and support the general idea that identity is established by combining subprograms involving cascades of transcription factors, which specify distinct components of neuronal phenotype.
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Division of Biology, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
Tiveron
M C
MC
Anderson
D J
DJ
D000818:Animals; D017776:Autonomic Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D029721:Drosophila Proteins; D005260:Female; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins; D010641:Phenotype; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D016212:Transforming Growth Factor beta
D051792:Basic Helix-Loop-Helix Proteins; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C499317:Ascl1 protein, mouse; C499318:Ascl1 protein, rat; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C491061:PHOX2A protein, human; C491060:Phox2a protein, mouse; C100935:Phox2a protein, rat; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C495001:Ret protein, rat