Antiapoptotic role of the p38 mitogen-activated protein kinase–myocyte enhancer factor 2 transcription factor pathway during neuronal differentiation

^*Center for Neuroscience and Aging, The Burnham Institute, La Jolla, CA 92037; and ^†Cerebrovascular and NeuroScience Research Institute, Brigham and Women's Hospital, Division of Neuroscience, Children's Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA 02115

Edited by Floyd E. Bloom, The Scripps Research Institute, La Jolla, CA, and approved April 26, 2000 (received for review November 17, 1999)

Abstract

Myocyte enhancer factor 2 (MEF2) is in the MADS (MCM1agamous-deficiens-serum response factor) family of transcription factors. Although MEF2 is known as a myogenic factor, the expression pattern of the MEF2 family of genes (MEF2A-D) in developing brain also suggests a role in neurogenesis. Here we show that transfection with MEF2C, the predominant form in mammalian cerebral cortex, induces a mixed neuronal/myogenic phenotype in undifferentiated P19 precursor cells. During retinoic acid-induced neurogenesis of these cells, a dominant negative form of MEF2 enhances apoptosis but does not affect cell division. The mitogen-activated protein kinase p38α activates MEF2C. Dominant negative p38α also enhances apoptotic death of differentiating neurons, but these cells can be rescued from apoptosis by coexpression of constitutively active MEF2C. These findings suggest that the p38α/MEF2 pathway prevents cell death during neuronal differentiation.

Footnotes

↵ ‡ To whom reprint requests should be addressed at: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. E-mail: slipton{at}burnham.org.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.130502697.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.130502697
Abbreviations:

bHLH,

basic helix–loop–helix;

CNS,

central nervous system;

GFP,

green fluorescent protein;

MAP,

mitogen-activated protein;

MAP2,

microtubule-associated protein 2;

MEF2,

myocyte enhancer factor 2;

pGK,

phosphoglycerate kinase;

TUNEL,

terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling