Extracellular signal-regulated kinase (ERK) 5 is necessary and sufficient to specify cortical neuronal fate

doi:10.1073/pnas.0603373103

Extracellular signal-regulated kinase (ERK) 5 is necessary and sufficient to specify cortical neuronal fate

*Toxicology Program, Department of Environmental and Occupational Health Sciences, and
^†Department of Pharmacology, University of Washington, Seattle, WA 98195

Communicated by Edwin G. Krebs, University of Washington School of Medicine, Seattle, WA, April 26, 2006 (received for review January 23, 2006)

Abstract

Multipotent cortical progenitor cells differentiate into neurons and glial cells during development; however, mechanisms governing the specification of progenitors to a neuronal fate are not well understood. Although both extrinsic and intrinsic factors regulate this process, little is known about kinase signaling mechanisms that direct neuronal fate. Here, we report that extracellular signal-regulated kinase (ERK) 5 is expressed and active in proliferating cortical progenitors. Lentiviral gene delivery of a dominant negative ERK5 or dominant negative MAP kinase kinase 5 reduced the number of neurons generated from rat cortical progenitor cells in culture, whereas constitutive activation of ERK5 increased the production of neurons. Furthermore, when cortical progenitor cells were treated with ciliary neurotrophic factor, which induces precocious glial differentiation, ERK5 activation still promoted neuronal fate while suppressing glial differentiation. Our data also indicate that ERK5 does not directly regulate proliferation or apoptosis of cultured cortical progenitors. We conclude that ERK5 is necessary and sufficient to stimulate the generation of neurons from cortical progenitors. These results suggest a previously uncharacterized function for ERK5 signaling during brain development and raise the interesting possibility that extrinsic factors may instruct cortical progenitors to become neurons by activating the ERK5 pathway.

Footnotes

^‡To whom correspondence should be addressed at:
Department of Environmental and Occupational Health Sciences, Box 357234, University of Washington, Seattle, WA 98195.
E-mail: zxia{at}u.washington.edu
Author contributions: L.L. and Z.X. designed research; L.L., P.C., G.A., Y.W., R.F., H.S., and M.X. performed research; L.L. and G.A. contributed new reagents/analytic tools; L.L. analyzed data; and L.L. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

ca,

constitutive active;

CNTF,

ciliary neurotrophic factor;

DIVn,

day in vitro n;

dn,

dominant negative;

En,

embryonic day n;

ERK,

extracellular signal-regulated kinase;

IRES,

internal ribosomal entry site;

MAP,

mitogen-activated protein;

MEK,

MAP kinase kinase;

wt,

wild type