Fig. 1.

The physiological functions of Pin1 in the nervous system. a Pin1 is implicated in neurodevelopment, where it tightly regulates neuronal differentiation and axonal growth. In particular, Pin1 is highly expressed during neurodevelopmental stages, where it controls cortical differentiation of neuron progenitor cells (NPCs), by acting on β-catenin pathway, without affecting gliogenesis. Moreover, Pin1 is required for the development of the central nervous system for axonal growth during embryonic development and for establishing a proper axonal connectivity, by controlling the adhesion and spread of the axonal growth cone. b Pin1 acts also as modulator of synaptic activity. At glutamatergic synapses, Pin1 is catalytically present in dendrites, where, under basal conditions, it inhibits protein translation, required for late LTP maintenance, and negatively regulates PSD95/GluN2B complex formation, as well as spine density, and NMDA-mediated synaptic transmission. At glycinergic synapses, Pin1 interacts with gephyrin and alters its overall conformation, thereby affecting the function of glycine receptors. At GABAergic synapses, it inhibits the ability of neuroligin 2 to interact with the scaffolding protein gephyrin. c Pin1 is a key context–dependent signal transducer of neuronal cell death and survival signals. In developing neurons, Pin1 binds and stabilizes JNK-phosphorylated forms of BIM_EL, protecting it from proteasomal degradation and thereby activating the mitochondrial cell death machinery via c-Jun. In addition, Pin1 overexpression overrides NGF-derived survival signals and triggers caspase-dependent neuronal cell death. Besides such pro-apoptotic action, Pin1 also mediates pro-survival effects: as shown by various observation, as reported in the text, and in in vitro experiments on oligodendrocytes, where Pin1 exerts an anti-apoptotic function by binding and stabilizing the anti-apoptotic Bcl-2 family protein Mcl-1, a pro-survival member of the Bcl-2 family, in the cytosol