The role of ATP signaling in the migration of intermediate neuronal progenitors to the neocortical subventricular zone.

Most neurons of the cerebral cortex are generated in the germinal zones near the embryonic cerebral ventricle and migrate radially to the overlying cortical plate. Initially, all dividing cells are attached to the surface of the embryonic ventricle (ventricular zone) until a subset of dividing cells (basal or intermediate neuronal progenitors, INPs), recognized by their immunoreactivity to Tbr2, detach from the ventricular surface and migrate a short distance to establish a secondary proliferative compartment (the subventricular zone). The mechanism that regulates migration of the Tbr2(+) INPs from the ventricular to the subventricular zones is unknown. Here, we show that INPs, unlike the postmitotic neurons that tend to lose the ATP response, continue to express the purinergic P2Y1 receptor. Furthermore, blocking ATP signaling by the P2Y1 blockers, MRS2176, suramin, and apyrase, reduces Ca(2+) transients and retards INP migration to the subventricular zone. In addition, genetic knockdown of the P2Y1 receptor by in vivo application of short hairpin RNA selectively impairs the migration of INPs to the subventricular zone. Together, these results suggest that intercellular ATP signaling is essential for the migration of INPs and the proper formation of the subventricular zone. Interference of ATP signaling or abnormal Ca(2+) fluctuations in INPs may play a significant role in variety of genetic or acquired cortical malformations.