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

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Signaling

Background:

• Aberrant signaling in the Raf/MEK/ERK (ERK/MAPK) pathway is linked to RASopathies and autism.
• Understanding ERK/MAPK signaling in neocortical development is essential for addressing these conditions.

Purpose of the Study:

• To investigate the specific functions of ERK/MAPK signaling in developing neocortical excitatory neurons.
• To elucidate the role of this pathway in neuronal morphology, survival, and circuit formation.

Main Methods:

• Genetic manipulation of Map2k1/2 (Mek1/2) to alter ERK/MAPK signaling in developing cortical neurons.
• Analysis of neuronal morphology, survival, axonal development, and intrinsic excitability.
• Assessment of synaptic function and gene expression (Arc).

Main Results:

• ERK/MAPK signaling is critical for the morphological development and survival of layer 5 Ctip2(+) neurons.
• Loss of Map2k1/2 impairs corticospinal tract formation and leads to corticospinal neuron apoptosis.
• ERK/MAPK hyperactivation reduces axon elongation but enhances arborization in layer 5 neurons.
• Map2k1/2 deletion affects axonal outgrowth in layer 2/3 neurons, reduces Arc expression, and increases intrinsic excitability in both layers.
• Synaptic excitation-inhibition balance is disrupted by Map2k1/2 deletion.

Conclusions:

• ERK/MAPK signaling has selective roles in the development of layer 5 cortical circuits.
• The pathway broadly influences cortical pyramidal neuron excitability and synaptic function.
• These findings highlight the complex involvement of ERK/MAPK signaling in neurodevelopmental processes and disorders.