The septin cytoskeleton is required for morphogenesis of pyramidal neurons

Megan R. Radler

doi:10.17918/00001447

Neurons are dramatically polarized cells, and are the functional subunit of the nervous system. Their polarized morphology is crucial to their function. Pyramidal neurons, which are the dominant cell type in the cerebral cortex, hippocampus, and amygdala, share several characteristic qualities: a triangular-shaped cell body, an apical dendrite that bifurcates before a tuft of processes, and a basal arbor, containing multiple dendrites and a single thin axon. Though the cytoskeletal rearrangements underlying neurite initiation, polarization, and neuron morphogenesis are known, how these processes are regulated remains understudied. In this thesis, I examine how septins, a family of GTP-binding proteins, modulate the actin and microtubule cytoskeletons in neuronal morphogenesis. In the first part of this thesis, I describe a novel wreath-like network of septin filaments that is present in the soma of neurons before they have formed neurites. I show how this wreath network, which contains septins 5, 11, and 7, acts to modulate the protrusive and contractile forces of actin by scaffolding non-muscle myosin IIB at the base of filopida, and inhibiting the localization of Arp2/3 outside of the branched actin network in the circumferential lamella. Neurons developing in these conditions have temporal delays in polarization, enlarged cell bodies, and an excess of over-branched neurites. After continued culture under these conditions, matured neurons show defects in apical-basal polarity establishment. In addition to characterizing this phenotype in cultured rat hippocampal neurons, Sept7 depletion in mouse cortical neurons in vivo resulted in enlarged, misshapen neuronal cell bodies, and altered cell body and apical dendrite orientation in relation to the pial surface. Taken together, these data suggest a universal mechanism for modulating actin protrusion and contractility during neurite development, and displays how early perturbations in neuronal morphogenesis underlie neurodevelopmental complications. In the second portion of my dissertation, I describe my contributions to projects that examined how septins tune microtubule dynamics and coordinate interactions between the actin and microtubule cytoskeletons. The cell body of neurons prior to neurite formation and neuronal growth cones share large regions of actin and microtubule overlap, In both of these contexts, but particularly in growth cones, fine tuning of microtubule dynamics, and the coupling of actin dynamics to the microtubule cytoskeleton are critical. I show that septin filaments interact with microtubule plus ends to dampen dynamics more significantly than actin filaments within growth cones. Additionally, septins localize within the transition zone of growth cones, colocalizing with actin and microtubule filaments. In conditions where septin filaments are depleted, neuronal growth cones are smaller, and are more frequently collapsed. This data shows that septins are required for maintenance of growth cone structure through coordination of the actin and microtubule cytoskeletons. Together, this work describes how septins localize within pyramidal neurons at different stages of development. It explores how septins localizing in different compartments and at different stages of development regulate cytoskeletal dynamics.

The septin cytoskeleton is required for morphogenesis of pyramidal neurons

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The septin cytoskeleton is required for morphogenesis of pyramidal neurons

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