The assembly of neural circuits during development is coordinately governed by extrinsic and intrinsic mechanisms that control different aspects of neuronal differentiation. Transcription factors have emerged as critical regulators of general as well as specific traits of neuronal identity including polarization,
migration, axon growth and guidance, dendrite morphology and targeting, and synaptogenesis. Identification of additional transcriptional regulators that mediate distinct aspects of neuronal morphogenesis together with their upstream
regulatory pathways and downstream effectors is instrumental for defining mechanisms responsible for establishment of normal neuronal connectivity during development and perturbation thereof in disease.
In this thesis, using Drosophila as a model system, I characterized a novel neuronal function of the forkhead domain-containing transcription factor FoxO as a negative regulator of synaptic microtubule (MT) stability. foxO loss-of-function
(LOF) neuromuscular junctions (NMJs) are characterized by elevated MT stability, which underlies defects in gross synaptic morphology and function. Overexpression of wild-type FoxO moderately destabilizes the synaptic MT network, while overexpression of constitutively-nuclear FoxO drives severe MT destabilization at the NMJ. Additionally, I show that FoxO protein levels in the
CNS are decreased in response to developmental as well as acute MT
disruption. In case of the latter, FoxO downregulation is independent of the DLK MAPK injury signaling pathway and requires Akt. Consistently, levels of activated phospho-Akt (p-Akt) are increased in the CNS and peripheral nerves following
acute pharmacological MT destabilization. Thus, this work identifies a novel cell-intrinsic mechanism that contributes to neuronal differentiation during development and regulates cellular homeostasis in response to cytoskeletal perturbation.