Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex

Abstract

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.DOI: http://dx.doi.org/10.7554/eLife.11123.001

Laminar specific gene expression reveals differences in postnatal laminar maturation in mouse auditory, visual, and somatosensory cortex

“…And later, in mouse S1, retrogradely labeled layer 6 corticothalamic projection neurons were found to express a low level of Ctip2 in layer 6 at P4 (McKenna et al, ). Ctip2 was also expressed in layer 6 as well as in layer 5 of mouse visual cortex at P14 (Xing et al, ). Consistent with these reports, we found Ctip2 expression in retrogradely labeled corticothalamic neurons in SCx and VCx, and we extended these studies to ACx.…”

“…And later, in mouse S1, retrogradely labeled layer 6 corticothalamic projection neurons were found to express a low level of Ctip2 in layer 6 at P4 (McKenna et al, 2011). Ctip2 was also expressed in layer 6 as well as in layer 5 of mouse visual cortex at P14 (Xing et al, 2016).…”

Divergent effects of intrinsically active MEK variants on developmental Ras signaling

“…To summarize, the divergent effects of activating mutations are not limited to MEK and can be induced by activating perturbations in other components of the RTK pathway. Indeed, a few studies have associated loss-of-function phenotypes with activating mutations in the Ras pathway 21,22 . Our results suggest that such phenotypes may result from attenuated signaling levels.…”

Hyperactive MEK1 signaling in cortical GABAergic neurons causes embryonic parvalbumin-neuron death and defects in behavioral inhibition

“…In the embryonic ventricular zone, neural progenitors typically show high levels of P-ERK1/2 relative to immature post-mitotic neurons (Pucilowska et al, 2018; Stanco et al, 2014). In adult cortices, elevated P-ERK1/2 labeling is enriched in a heterogeneous set of excitatory PNs, primarily in layer 2, and plays a critical role in long-range PN development (Cancedda et al, 2003; Gauthier et al, 2007; Holter et al, 2019; Pham et al, 2004; Pucilowska et al, 2012; Suzuki et al, 2004; Xing et al, 2016). The activation of ERK1/2 in CINs has not been well characterized.…”