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.

Disrupted ERK1/2 (MAPK3/MAPK1) MAPK signaling has been associated with several developmental syndromes in humans; however, mutations in ERK1 or ERK2 have not been described. We demonstrate haplo-insufficient ERK2 expression in patients with a novel Ϸ1 Mb micro-deletion in distal 22q11.2, a region that includes ERK2. These patients exhibit conotruncal and craniofacial anomalies that arise from perturbation of neural crest development and exhibit defects comparable to the DiGeorge syndrome spectrum. Remarkably, these defects are replicated in mice by conditional inactivation of ERK2 in the developing neural crest. Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. Our findings demonstrate that mammalian neural crest development is critically dependent on a RAF/MEK/ERK/ serum response factor signaling pathway and suggest that the craniofacial and cardiac outflow tract defects observed in patients with a distal 22q11.2 micro-deletion are explained by deficiencies in neural crest autonomous ERK2 signaling.22q11 microdeletion ͉ human syndromes ͉ MAP kinase

The ERK MAP kinase signaling cascade plays critical roles in brain development, learning, memory, and cognition. It has recently been appreciated that mutation or deletion of elements within this signaling pathway leads to developmental syndromes in humans that are associated with impaired cognitive function and autism. Here, we review recent studies that provide insight into the biological roles of the ERKs in the brain that may underlie the cognitive deficits seen in these syndromes.