Cell and Molecular Biology of the Spindle Matrix

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Abstract

The concept of a spindle matrix has long been proposed to account for incompletely understood features of microtubule spindle dynamics and force production during mitosis. In its simplest formulation, the spindle matrix is hypothesized to provide a stationary or elastic molecular matrix that can provide a substrate for motor molecules to interact with during microtubule sliding and which can stabilize the spindle during force production. Although this is an attractive concept with the potential to greatly simplify current models of microtubule spindle behavior, definitive evidence for the molecular nature of a spindle matrix or for its direct role in microtubule spindle function has been lagging. However, as reviewed here multiple studies spanning the evolutionary spectrum from lower eukaryotes to vertebrates have provided new and intriguing evidence that a spindle matrix may be a general feature of mitosis.

Introduction

A mitotic spindle is present in all known eukaryotic cells and its function is essential for chromosomal segregation and cell division to occur (Mitchison and Salmon, 2001). The spindle apparatus is a complex molecular machine known to be made up of polymerized tubulin and various associated motor proteins (Gadde 2004, Karsenti 2001, Sharp 2000a). Although much work has been directed toward understanding mitotic spindle apparatus structure and function, it is still unclear what directs and stabilizes the assembly of the spindle. Furthermore, although numerous models have been proposed for how the spindle apparatus may transmit forces, none of these models have been able to account for all the experimentally observed properties of spindle behavior (Bloom 2002, Gadde 2004, Kapoor 2002, Mitchison 2001, Scholey 2001, Wittmann 2001); especially, the discovery of microtubule flux and the constant treadmilling of tubulin dimers toward the poles (Cassimeris 1988, Mitchison 1989, Mitchison 2001, Rogers 2005, Sawin 1991, Sawin 1994) have made it difficult to model how forces are generated to actually move chromosomes on the basis of a metastable structure not anchored in place. For these reasons and based on theoretical considerations of the requirement for force production at the spindle, the concept of a spindle matrix has long been proposed (Johansen 2002, Pickett‐Heaps 1982, Pickett‐Heaps 1997, Wells 2001). The spindle matrix is hypothesized to provide a stationary or elastic molecular matrix that can provide a substrate for motor molecules to interact with during microtubule sliding and which can stabilize the spindle during force production (Pickett‐Heaps et al., 1997) (Fig. 4.1). Molecules forming a spindle matrix complex would be expected to exhibit several characteristics: (1) they should associate together to form a true fusiform structure coaligned with the microtubule spindle; (2) they should remain associated, forming a polymerized complex in the absence of microtubules; (3) perturbation of one or more of the components should affect spindle assembly and/or function; and (4) one or more members of the complex should interact with microtubules or microtubule‐associated molecules such as motor proteins. Such a matrix could also be envisioned to have the added properties of helping to organize and stabilize the microtubule spindle as well as the midbody, an electron dense body implicated in cytokinesis. Whereas the spindle matrix is an attractive concept, for many years there has been little direct experimental evidence for such a structure, and its molecular nature has remained enigmatic. However, a number of studies in Drosophila (Qi 2004, Qi 2005, Rath 2004, Walker 2000) as well as in vertebrates (Chang 2004, Mitchison 2005, Tsai 2006) have revived interest in the spindle matrix. Here we review evidence for the existence of a spindle matrix and its possible molecular composition in the context of microtubule spindle dynamics and force production.

Section snippets

Microtubule Spindle Dynamics and Force Production

The mitotic spindle is a dynamic, complex macromolecular machine constantly being remodeled during the progression through the stages of mitosis (prophase, prometaphase, metaphase, anaphase, and telophase). Most research to date has focused on two classes of molecules that play critical roles in transducing the forces necessary to align and separate chromosomes precisely to two daughter nuclei, namely microtubules and motor proteins (Kapoor 2002, Karsenti 2001, Mitchison 2001, Sharp 2000a,

Evidence for a Spindle Matrix

Some of the first experimental observations that hinted at the existence of a spindle matrix were from the early experiments of Goldman 1969, Forer 1969, who found that the volume of the nonmicrotubule portion of the spindle was much greater than that of microtubules. That this could correspond to a “spindle matrix” was suggested by data indicating that birefringence in the spindle originates from nonmicrotubule, as well as from microtubule, components. Similar conclusions were made from EM

Concluding Remarks

As reviewed here, multiple studies spanning the evolutionary spectrum from lower eukaryotes to vertebrates have provided new and intriguing evidence that a spindle matrix may be a general feature of mitosis. Nonetheless, definitive evidence for its molecular nature and for its role in microtubule spindle function is still lacking. Considering the diversity of potential and unrelated spindle matrix molecules so far described, the possibility exists that different molecules may have attained the

Acknowledgments

We thank Drs. A. Forer, T. Spurck, J. D. Pickett‐Heaps, and Dr. D. Sharp for generously providing micrographs. We also thank Dr. A. Forer, H. Maiato, and the members of our laboratory for critical reading of the manuscript and for helpful comments. The authors' work on the spindle matrix is supported by NSF grant MCB0445182.

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