βIII spectrin is required for orthogonal wiring between Purkinje cell dendrites and granule cell axons in the murine cerebellar circuit

Abstract

The mechanism underlying the geometrical patterning of axon and dendrite wiring remains elusive, despite its critical importance in the formation of functional neural circuits. Cerebellar Purkinje cell (PC) arborizes a typical planar dendrite, which forms an orthogonal network with granule cell (GC) axons. By using electrospun nanofiber substrates, we reproduce the perpendicular contacts between PC dendrites and GC axons in culture. In the model system, PC dendrites show preference to grow perpendicular to aligned GC axons, which presumably contribute to the planar dendrite arborization in vivo. We show that {beta}III spectrin, a causal gene for spinocerebellar ataxia type 5 (SCA5), is required for the biased growth of dendrites. {beta}III spectrin deficiency causes actin mislocalization and excessive microtubule invasion in dendritic protrusions, resulting in abnormally oriented branch formation. Furthermore, disease-associated mutations affect the ability of {beta}III spectrin to control dendrite orientation. These data indicate that {beta}III spectrin organizes the dendritic cytoskeleton and thereby regulates the oriented growth of dendrites with respect to the afferent axons. Summary statement{beta}III spectrin suppress the microtubule dynamics at the neuronal dendrite to inhibit the abnormal lateral branching, which causes misoriented branch formation.