Formin3 regulates dendritic architecture via microtubule stabilization and is required for somatosensory nociceptive behavior

The acquisition, maintenance and modulation of dendritic architecture are critical to neuronal form, plasticity and function. Morphologically, dendritic shape impacts functional connectivity and is largely mediated by organization and dynamics of cytoskeletal fibers that provide the underlying scaffold and tracks for intracellular trafficking. Identifying molecular factors that regulate dendritic cytoskeletal architecture is therefore important in understanding mechanistic links between cytoskeletal organization and neuronal function. In a neurogenomic-driven genetic screen of cytoskeletal regulatory molecules, we identified Formin3 (Form3) as a critical regulator of cytoskeletal architecture in Drosophila nociceptive sensory neurons. Form3 is a member of the conserved Formin family of multi-functional cytoskeletal regulators and time course analyses reveal Form3 is cell-autonomously required for maintenance of complex dendritic arbors. Cytoskeletal imaging demonstrates form3 mutants exhibit a specific destabilization of the dendritic microtubule (MT) cytoskeleton, together with defective dendritic trafficking of mitochondria, satellite Golgi and the TRPA channel Painless. Biochemical studies reveal Form3 directly interacts with MTs via FH1-FH2 domains and promotes MT stabilization via acetylation. Neurologically, mutations in human Inverted Formin 2 (INF2; ortholog of form3) have been causally linked to Charcot-Marie-Tooth (CMT) disease. CMT sensory neuropathies lead to impaired peripheral sensitivity. Defects in form3 function in nociceptive neurons results in a severe impairment in noxious heat evoked behaviors. Expression of the INF2 FH1-FH2 domains rescues form3 defects in MT stabilization and nocifensive behavior revealing conserved functions in regulating the cytoskeleton and sensory behavior thereby providing novel mechanistic insights into potential etiologies of CMT sensory neuropathies.