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Neurology & Neuroscience
IGF-1 Driven Regenerative Neurogenesis Requires a Novel RIT1 GTPase-SOX2 Cascade
Douglas Andres
Insulin-like growth factor 1 (IGF-1) is known to have diverse effects on brain structure and function, including the promotion of stem cell proliferation and neurogenesis in the adult dentate gyrus. … However, the intracellular pathways downstream of the IGF-1 receptor that contribute to these diverse physiological actions remain relatively uncharacterized. Here, we demonstrate that the Ras-related GTPase, RIT1, plays a critical role in IGF-1-dependent neurogenesis. Studies in hippocampal neuronal precursor cells (HNPCs) demonstrate that IGF-1 stimulates a RIT1-dependent increase in Sox2 levels, resulting in pro-neural gene expression and increased cellular proliferation. In this novel cascade, RIT1 stimulates Akt-dependent phosphorylation of Sox2, leading to its stabilization and transcriptional activation. Accordingly, Sox2-dependent hippocampal neurogenesis is significantly blunted following IGF-1 infusion in transgenic knockout (RIT1-/-) mice. Consistent with a role for RIT1 in the modulation of activity-dependent plasticity, exercise-mediated potentiation of hippocampal neurogenesis is also diminished in RIT1-/- mice. Taken together, these data identify the previously uncharacterized IGF1-RIT1-Akt-Sox2 signaling pathway as a key component of neurogenic niche sensing, contributing to the regulation of neural stem cell homeostasis.
Cellular and molecular dissection of neuromorphological deficits underlying ADNP syndrome and autism spectrum disorder
Kazuhito Toyooka
Activity‐dependent neuroprotective protein (ADNP) is shuttled to the cytoplasm to promote neuronal morphogenesis and functional cortical connectivity. Defective neuritogenesis is a contributing pathogenic … mechanism behind a variety of neurodevelopmental disorders. Mutations in ADNP are among the most frequent underlying autism spectrum disorder. Adnp has a suggested role in neurite formation, but if defective neuritogenesis underlies the pathology of ADNP syndrome has yet to be explored. We found that Adnp knockdown using in utero electroporation of mouse layer 2/3 pyramidal neurons in the somatosensory cortex leads to neurite formation defects beginning at P0. We used ex vivo live imaging and found severe flaws in cellular dynamics in Adnp deficient neurons. These include failure of neurite retraction, slow growth speed, increased neurite stabilization, and intracellular swellings. These defects are sustained throughout development. At P15, we noted increased basal dendrite number, axon length, and interhemispheric axon innervation. Slight changes to neurite morphology can lead to significant scale changes in brain connectivity and function, which can have behavioral consequences. To assess potential changes to neuronal function, we performed ex vivo calcium imaging which revealed that Adnp deficient neurons were hyperexcitable. To further probe changes to neuronal activity, we utilized GRAPHIC, a novel synaptic tracing technology, to assess cortico‐cortical connectivity. We found increased interhemispheric connectivity between Adnp deficient layer 2/3 pyramidal neurons. To probe the molecular mechanism of changes to neuronal morphology, we performed a localization analysis of Adnp. We found that Adnp is shuttled from the nucleus to the cytoplasm upon neurite formation, and a 14‐3‐3 inhibitor, difopein, can block this shuttling. We also found that Adnp binds nuclear‐cytoplasmic shuttle 14‐3‐3ε. We conclude that Adnp is shuttled to the cytoplasm by 14-3-3ε, where it regulates neurite formation, maturation, and functional cortical connectivity upon neuritogenesis.
