Mutation of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) substrate-docking site in the developing brain causes microcephaly with abnormal brain morphogenesis independently of Akt, leading to impaired cognition and disruptive behaviors

摘要

The phosphoinositide 3-kinase (PI 3-kinase)/Akt signaling pathway plays essential roles during neuronal development. The 3-phosphoinositide-dependent protein kinase 1 (PDK1) coordinates the PI 3-kinase signals by activating twenty three kinases of the AGC family including Akt. Phosphorylation of a conserved docking site in the substrate is a requisite for PDK1 to recognize, phosphorylate and activate most of these kinases, with the exception of Akt. We exploited this differential mechanism of regulation by generating neuronal-specific conditional knock-in mice expressing the mutant form of PDK1 L155E in which the substrate-docking site binding motif, termed the PIF-pocket, was disrupted. As a consequence, activation of all the PDK1 substrates tested excluding Akt was abolished. Mice exhibited microcephaly, altered cortical layering and reduced circuitry, leading to cognitive deficits and exacerbated disruptive behavior combined with diminished motivation. The abnormal patterning of the adult brain arise from the reduced ability of the embryonic neurons to polarize and extend their axons, therefore highlighting the essential roles that the PDK1 signaling beyond Akt plays in mediating the neuronal responses that are instructive for brain development.