The Mitogen Activated Protein kinases, ERK1 and ERK2 are critical intracellular signaling intermediates in proliferation and differentiation. ERK1/2 are also essential for memory, learning, and synaptic plasticity in the brain. ERK1/2 activity in neural progenitor cells (NPCs) is required for neuronal cell fate determination; yet little is known about their isoform-specific functions during neural development. We have previously shown that inactivation of ERK1 does not initiate severe phenotypic or behavioral deficits in mice, suggesting a redundant role for ERK2. Inactivation of ERK2 causes mice to die during embryogenesis. We have therefore examined the role of ERK2 and the combined actions of both isoforms in neural development by targeted and conditional inactivation of mapk3/ERK1 and mapk1/ERK2 in murine NPCs. Loss of ERK2 alone resulted in a reduction in cortical thickness attributable to impaired proliferation of NPCs and the generation of fewer neurons. Mutant NPCs remained in an undifferentiated state until gliogenic stimuli induced their differentiation, resulting in the generation of more astrocytes. The ERK2 mutant mice displayed profound deficits in associative learning. Importantly, we identified patients with a 1 Mb microdeletion on chromosome 22q11.2 encompassing the MAPK1/ERK2 gene. These children have reduced ERK2 levels and 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.
Simultaneous inactivation of both ERK1 and ERK2 (ERK1/2 DKO mice) lead to a slightly more severe phenotype than loss of ERK2 alone; however, the loss of both isoforms did not significantly alter the composition of the cortex. ERK1/2 DKO mice display similar changes in cell fate determination as ERK2 conditional knockouts where fewer neurons are generated and a greater number of NPCs remain undifferentiated. These changes are due to elevated levels of p27 and reductions in cyclin D2. Our findings indicate that in vivo, ERK1 can compensate for ERK2 late in neurogenesis, but that the normal function of ERK1 in neural development is subordinate to ERK2. Moreover, ERK1/2 are indispensable for proper neural progenitor cell function as well as learning and cognition.