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Published February 15, 1998 | Published
Journal Article Open

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.

Additional Information

© 1998 by Company of Biologists. Accepted 17 November 1997: published on WWW 22 January 1998. We are grateful to Drs Jean-François Brunet and Christo Goridis for sharing their unpublished results, for providing Phox2a antibodies and cDNA probes, and for helpful e-mail discussions. We acknowledge the original observations of Dr Lukas Sommer that expression of Phox2 mRNA is lost in Mash1 -/- mutants. We thank Ms Pat White for contributing to in situ hybridization experiments, Steven M. Padilla for plasmid preparation, Ling Wang for preparation of culture medium, and members of the Anderson laboratory for helpful discussions. D.J.A. is an Investigator of the Howard Hughes Medical Institute.

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