PDF(Pubmed)
Abstract：
Abnormal extracellular signal-regulated kinase 1/2 (ERK1/2, encoded by Mapk3 and Mapk1, respectively) signaling is linked to multiple neurodevelopmental diseases, especially the RASopathies, which typically exhibit ERK1/2 hyperactivation in neurons and non-neuronal cells. To better understand how excitatory neuron-autonomous ERK1/2 activity regulates forebrain development, we conditionally expressed a hyperactive MEK1 (MAP2K1) mutant, MEK1S217/221E, in cortical excitatory neurons of mice. MEK1S217/221E expression led to persistent hyperactivation of ERK1/2 in cortical axons, but not in soma/nuclei. We noted reduced axonal arborization in multiple target domains in mutant mice and reduced the levels of the activity-dependent protein ARC. These changes did not lead to deficits in voluntary locomotion or accelerating rotarod performance. However, skilled motor learning in a single-pellet retrieval task was significantly diminished in these MEK1S217/221E mutants. Restriction of MEK1S217/221E expression to layer V cortical neurons recapitulated axonal outgrowth deficits but did not affect motor learning. These results suggest that cortical excitatory neuron-autonomous hyperactivation of MEK1 is sufficient to drive deficits in axon outgrowth, which coincide with reduced ARC expression, and deficits in skilled motor learning. Our data indicate that neuron-autonomous decreases in long-range axonal outgrowth may be a key aspect of neuropathogenesis in RASopathies.
摘要：
异常的细胞外调节激酶1/2（ERK1/2）信号与多种神经发育疾病有关。尤其是放射病，通常在神经元和非神经元细胞中表现出ERK1/2过度激活。为了更好地理解兴奋性神经元自主ERK1/2活动如何调节前脑发育，我们有条件地在皮质兴奋性神经元中表达过度活跃的MEK1S217/221E。MEK1S217/221E表达导致皮质轴突ERK1/2持续过度激活，但不是在体/核中。我们注意到突变体中多个靶结构域的轴突乔化减少，活性依赖性基因的表达减少，ARC.这些变化不会导致自愿运动或加速旋转杆性能的缺陷。然而,在这些MEK1S217/221E突变体中，在单颗粒检索任务中熟练的运动学习显着减少。MEK1S217/221E表达限制在V层皮层神经元上，概括了轴突生长缺陷，但没有影响运动学习。这些结果表明，MEK1的皮质兴奋性神经元自主过度激活足以驱动轴突生长缺陷，这与减少的ARC表达一致，以及熟练运动学习的缺陷。我们的数据表明，远距离轴突生长的神经元自主减少可能是RASopathies神经发病机制的关键方面。
