Analyses of the function and regulation of the PTEN suppressor during early brain development

Project Leader: Britta Eickholt e-mail

 

The PTEN tumor suppressor gene is one of the most frequently mutated genes in glioblastomas, and has been demonstrated to restrict neural stem progenitor cell proliferation. Human germline PTEN mutations or conditional deletions of PTEN in mice have also been associated with neurodevelopment disorders such as macrocephaly, ataxia, seizures, mental retardation and autism. PTEN exerts its function predominantly through negative regulation of the growth, proliferative, and survival signals transduced by phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphoinositide 3-kinase (PI3K) signaling. However, PTEN has other potential mechanisms of action including functions involving its protein phosphatase activity and functions in cellular compartments other than the cell membrane. The physiological significance of these PIP3-independent roles, especially in neurons, remains largely unclear. We have identified and initially characterized a sub-cellular pool of phosphorylated PTEN (pT366-PTEN) in neural progenitor cells, which resides specifically at the centrosome and dynamically distributes to the mitotic spindle apparatus during the different phases of mitosis. In the research proposed here, we will analyze the precise regulation and consequence of pT366-PTEN during neurogenesis. In addressing this goal, we will provide detailed analyses of the molecular and spatialtemporal characteristics of pT366-PTEN during cell cycle progression. We will systematically examine in neural progenitor cells the kinase signaling input onto PTEN T366 through epistasis experiments. In pursuing these strategies we will exploit a combination of genetic and pharmacological approaches, as well as transient manipulation in both neuronal cell and mouse models. Our work will clarify the significance of a centrosomal PTEN function during neurogenesis, providing new insights into the etiology of neurodevelopmental diseases related to the dysfunction of the centrosome.