Role of formin 2 in actin microtubule coordination during axonal pathfinding and it s characterization in axonal branching

Abstract

Neural circuits are formed by directed translocation of axonal growth cones to their synaptic targets and specific patterns of branching The axon with the growth cone at the tip moves in a directed fashion by sensing the environmental cues through structures like the filopodia As the neuron reaches its target tissue it innervates the tissue to form multiple connections This is achieved by the arborization of the terminal end of the axon or by collateral branching of the axon These processes of outgrowth guidance and branching are driven by active and coordinated remodelling of the underlying cytoskeletal components One such cytoskeletal regulator is Formin 2 Fmn2 an actin nucleator which is highly expressed in the developing and adult central nervous system Leader and Leder 2000 and has been implicated in cognition Law et al 2014 Ag 237 s Balboa et al 2017 Recent studies from our lab have provided glimpses into the mechanism of Fmn2 function during the development of the nervous system Fmn2 is involved in maintaining optimum outgrowth speed and directionality of migration Moreover deficiency of Fmn2 resulted in pathfinding defects of spinal commissural neurons Sahasrabudhe et al 2016 Since axonal pathfinding requires coordination between actin and microtubule cytoskeletons this study investigated the role of Fmn2 in mediating actin microtubule crosstalk We find that Fmn2 facilitates the exploration of microtubules into the peripheral domain of the growth cone In the filopodia Fmn2 stabilizes the microtubules most likely by physically coupling themto the F actin bundles This coupling appears to occur through the tail region of Fmn2 which binds to both actin and microtubule In the absence of Fmn2 disruption of actin microtubule crosstalk in filopodia results in deficits in sensing and or turning that underlie the axon guidance defects Along with the requirement of Fmn2 in the growth cone Fmn2 was found to be involved in axonal collateral branching Axonal branching is an important component of connectivity