Expression delay in MEF2A-associated pathway in human PFC development. (A) Schematic representation of MEF2A-associated pathway in cortical neurons. MEF2A can be activated by BDNF, which is also a target of MEF2A (Liu et al. 2003; Shalizi et al. 2003; Flavell et al. 2008), or calcium-dependent calcineurin (Flavell et al. 2006). Activity-dependent regulation of MEF2A transcription promotes the expression of target genes, such as ARC (activity-regulated cytoskeletal associated protein) and SYNGAP1 (synaptic localized Ras GAP), to promote elimination of excitatory synapses (Flavell et al. 2006). Activity-dependent regulation of MEF2A can also promote the transcription of target genes, such as NR4A1, to inhibit the postsynaptic differentiation (Shalizi et al. 2006). SYP and DLG4 are the marker genes for presynapse and postsynapse (Masliah et al. 1990; Hunt et al. 1996). (B) Expression profiles of genes shown on panel A during human, chimpanzee, and macaque PFC development. Points represent individuals (red, human; blue, chimpanzee; green, macaque), lines show cubic spline curves. MEF2A, the activators of MEF2A (PPP3CB and BDNF), and the postsynaptic marker gene (DLG4) belong to module 1. Target genes of MEF2A (e.g., EGR), the presynaptic marker (SYP), and three neurotransmitters (glutamate [Glu], aspartate [Asp], and GABA) show human-specific expression delay resembling closely the module 1 profile.
