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The Journal of Neuroscience, July 2, 2008, 28(27):6983-6995; doi:10.1523/JNEUROSCI.0679-08.2008

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Development/Plasticity/Repair
Deletion of ERK2 Mitogen-Activated Protein Kinase Identifies Its Key Roles in Cortical Neurogenesis and Cognitive Function

Ivy S. Samuels,¹ J. Colleen Karlo,¹ Alicia N. Faruzzi,² Kathryn Pickering,³ Karl Herrup,⁴ J. David Sweatt,² Sulagna C. Saitta,³ and Gary E. Landreth¹

¹Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4928, ²Department of Neurobiology and McKnight Brain Institute, University of Alabama, Birmingham, Birmingham, Alabama 35294, ³Division of Human Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ⁴Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08855-8082

Correspondence should be addressed to Gary E. Landreth, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4928. Email: gel2{at}case.edu

The mitogen-activated protein (MAP) kinases ERK1 and ERK2 are critical intracellular signaling intermediates; however, little is known about their isoform-specific functions in vivo. We have examined the role of ERK2 in neural development by conditional inactivation of the murine mapk1/ERK2 gene in neural progenitor cells of the developing cortex. ERK MAP kinase (MAPK) activity in neural progenitor cells is required for neuronal cell fate determination. Loss of ERK2 resulted in a reduction in cortical thickness attributable to impaired proliferation of neural progenitors during the neurogenic period and the generation of fewer neurons. Mutant neural progenitor cells remained in an undifferentiated state until gliogenic stimuli induced their differentiation, resulting in the generation of more astrocytes. The mutant mice displayed profound deficits in associative learning. Importantly, we have identified patients with a 1 Mb microdeletion on chromosome 22q11.2 encompassing the MAPK1/ERK2 gene. These children, who have reduced ERK2 levels, exhibit microcephaly, impaired cognition, and developmental delay. These findings demonstrate an important role for ERK2 in cellular proliferation and differentiation during neural development as well as in cognition and memory formation.

Key words: MAP kinase; neurogenesis; cortical development; associative learning; intermediate progenitor cell; neural progenitor cell

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Received Feb. 14, 2008; revised May 11, 2008; accepted May 20, 2008.

Correspondence should be addressed to Gary E. Landreth, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4928. Email: gel2{at}case.edu

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