Allen Institute for Brain Science, Seattle, United States
George Reed Bjorklund
School of Life Sciences, Arizona State University, Tempe, United States
Xiaoyan Li
University of North Carolina Neuroscience Center, The University of North Carolina School of Medicine, Chapel Hill, United States
Yaohong Wu
University of North Carolina Neuroscience Center, The University of North Carolina School of Medicine, Chapel Hill, United States
Benjamin D Philpot
University of North Carolina Neuroscience Center, The University of North Carolina School of Medicine, Chapel Hill, United States; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Carolina Institute for Developmental Disabilities, The University of North Carolina School of Medicine, Chapel Hill, United States
William D Snider
University of North Carolina Neuroscience Center, The University of North Carolina School of Medicine, Chapel Hill, United States; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States; Carolina Institute for Developmental Disabilities, The University of North Carolina School of Medicine, Chapel Hill, United States
Jason M Newbern
School of Life Sciences, Arizona State University, Tempe, United States
Aberrant signaling through the Raf/MEK/ERK (ERK/MAPK) pathway causes pathology in a family of neurodevelopmental disorders known as 'RASopathies' and is implicated in autism pathogenesis. Here, we have determined the functions of ERK/MAPK signaling in developing neocortical excitatory neurons. Our data reveal a critical requirement for ERK/MAPK signaling in the morphological development and survival of large Ctip2+ neurons in layer 5. Loss of Map2k1/2 (Mek1/2) led to deficits in corticospinal tract formation and subsequent corticospinal neuron apoptosis. ERK/MAPK hyperactivation also led to reduced corticospinal axon elongation, but was associated with enhanced arborization. ERK/MAPK signaling was dispensable for axonal outgrowth of layer 2/3 callosal neurons. However, Map2k1/2 deletion led to reduced expression of Arc and enhanced intrinsic excitability in both layers 2/3 and 5, in addition to imbalanced synaptic excitation and inhibition. These data demonstrate selective requirements for ERK/MAPK signaling in layer 5 circuit development and general effects on cortical pyramidal neuron excitability.
