Pierre Vanderhaeghen, from the University of Brussels, described efforts to generate defined cortical circuits from hiPSCs (Espuny-Camacho et al., 2013). Their differentiation methods seemed to closely mirror embryonic development, as hiPSCs differentiated first to cortical progenitors, then to pioneer neurons, then to deep layer pyramidal neurons, and finally to upper-layer pyramidal neurons. Although the human timeline was drastically extended, this same pattern was observed in both mouse (1-week) and human (3-month) cells (Nagashima et al., 2014). Using a 3D default differentiation protocol in Matrigel (3DDM differentiation), which yields spheres for analysis within 21 days, Vanderhaegen’s group analyzed lines from subjects with autosomal recessive primary microcephaly (mutations in the ASPM gene) (also termed microcephaly primary hereditary [MCPH]). Just as ASPM mutations disrupt corticogenesis in the earliest stages, he reported increased neuronal differentiation, although with reduced cortical marker expression, as well as mitotic spindle deviations, in the mutant cells compared to controls. Such phenotypes were not detected in ASPM mutant mice, which display only mild microcephaly, suggesting that ASPM mechanisms of action may be in part species-specific, underscoring the importance of studying
