Regulation of Microtubule Severing by Katanin Subunits during Neuronal Development

Abstract

Katanin, the microtubule-severing protein, consists of a subunit termed P60 that breaks the lattice of the microtubule and another subunit termed P80, the functions of which are not well understood. Data presented here show that the ratio of P60 to P80 varies markedly in different tissues, at different phases of development, and regionally within the neuron. P80 is more concentrated in the cell body and less variable during development, whereas P60 often shows concentrations in the distal tips of processes as well as dramatic spikes in expression at certain developmental stages. Overexpression of P60 at various stages in the differentiation of cultured hippocampal neurons results in substantial loss of microtubule mass and a diminution in total process length. In comparison, overexpression of P80, which is thought to augment the severing of microtubules by P60, results in a milder loss of microtubule mass and diminution in process length. At the developmental stage corresponding to axogenesis, overexpression of P60 decreases the total number of processes extended by the neuron, whereas overexpression of P80 produces the opposite result, suggesting that the effects on neuronal morphology are dependent on the degree of microtubule severing and loss of polymer. The microtubules that occupy the axon are notably more resistant to depolymerization in response to excess P60 or P80 than microtubules elsewhere in the neuron, suggesting that regional differences in the susceptibility of microtubules to severing proteins may be a critical factor in the generation and maintenance of neuronal polarity.

Drosophila IKK-related kinase Ik2 and Katanin p60-like 1 regulate dendrite pruning of sensory neuron during metamorphosis

“…It is possible that some microtubuleassociated proteins (MAP) may preferentially bind to the microtubules in dendrites or those in axons and thus provide differential protection against the microtubule-severing activity of Kat-60L1. For example, in cultured rat hippocampal neurons, the microtubules in dendrites are more susceptible to excess activity of overexpressed Katanin p60 than those in axons (30), and the axonal Tau proteins protect axonal microtubules from severing by Katanin (31). The differential binding preference for microtubules in dendrites versus axons could also arise from regional posttranslational modification of MAPs.…”

KATNB1 in the human testis and its genetic variants in fertile and oligoasthenoteratozoospermic infertile men

“…Katanin can also sever microtubules as they emerge from the nucleating complex to produce short microtubule seeds that can be transported to other sites and re-polymerized in a process known as 'cut and run' . Katanin is essential for a wide range of functions in various organisms including for the regulation of spindle dynamics during cell division in Caenorhabditis elegans (McNally et al, 2006(McNally et al, , 2014, microtubule dynamics in developing rodent neurons (Ahmad et al, 1999;Karabay et al, 2004;Yu et al, 2005) and in plant cells (Nakamura et al, 2010), and for the assembly of flagella in Tetrahymena, Trypanosomes and mice (Sharma et al, 2007;Casanova et al, 2009;O'Donnell et al, 2012). Importantly, both Katnb1 and the p60-severing enzyme homolog Katnal1, have been shown to be essential for male fertility in the mouse Smith et al, 2012).…”

KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome

“…Structural microtubule associated proteins (MAPs) can also regulate microtubule dynamics . Overexpression of the most prominent axonal MAP, tau, compromises the ability of kinesin motor proteins to bind to microtubules (Mandelkow et al, 2003;Stamer et al, 2002), causing a cascade of events that can lead to the severing of microtubules themselves Qiang et al, 2006;Yu et al, 2005). Increasing data suggest that defects in microtubule based axonal transport may cause neural degeneration that is symptomatic of many human neurological disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) (Duncan and Goldstein, 2006).…”