The Study Of PDK1 In Regulation Neuronal Survival During Cortical Development

During brain development,numerous neurons is generated and a varying number of neurons die,and both immature and mature neurons are involved.The process of the elimination the overproduced neurons is necessary to optimize brain connectivity.Abnormal neuronal death regulation not only change cell composition and the neuronal connectivity but also alters cognition and so on.Abnormal neuronal will causes diseases such as cortical malformations,schizophrenia,autism spectrum disorders(ASDs)and some other diseases.Studies suggest that PI3K signaling plays very important roles in the diseases mentioned above,such as Akt,PI3K.PI3K signaling plays critical roles in cell proliferation,cell differentiation,cell metabolism and cell survival.The intact PI3K signaling pathway is very important to development and will maintain of functions in the whole body.The abruption of PI3K signaling causes a series of neurological and developmental diseases or cancer.PI3K-PDK1-Akt signaling pathway consists of several important components.The extracellular insulin and some other growth factors interact with their receptors,which cause the intracellular phosphorylation of PI3K and induce the generation of PIP3 from PIP2.PDK1(3-phosphoinositide dependent protein kinase 1)is recruited to the intracellular membrane by PIP3 via its PH domain and then phosphorylates Akt at the 308 threonine(Thr)residue.As one of the main regulation factors to the AGC families,PDK1 not only active Akt but also phosphorylate some other AGC kinase members such as p90 ribosomal S6 kinase 1/2(RSK1/2),p70 ribosomal S6 kinase(p70S6K),serum-and glucocorticoid-induced protein kinase(SGK)and protein kinase C(PKC)are substrates for PDK1 as well.Recent evidence has shown that PDK1,a key member in the PI3K signaling pathway,is associated with dementia.But how it exerts its role is controversial.On one hand,reduced PDK1 levels and impaired PI3K signaling were found in Alzheimer’s disease(AD)brain,suggesting a loss-of-function manner.On the other hand,another group reported that PDK1 activity was increased in AD brain,and that PDK1 inhibitor enhanced a-secretase activity and reduced amyloid plaques in APP transgenic(Tg)mouse models of AD,suggesting a gain-of-function mechanism.In this study,the Cre-loxP system was employed to generate a viable PDK1 cKO mouse model in which PDK1 is conditionally deleted in excitatory neurons and glial cells of the forebrain.We reported that PDK1 cKO mice displayed deficits in spatial learning and motor learning.We demonstrated that PDK1 cKO mice exhibited microcephaly associated with neuron loss and synaptic loss.We found that PDK1 cKO mice displayed deficient cortical layer morphology and increased apoptotic cell death.Furthermore,we showed that the downstream signaling of PDK1 was impaired in PDK1 cKO animals.Moreover,PDK1 cKO mice show decreased activities for Akt and mTOR.