Kevin F. O'Connell, Ph.D. : NIDDK

Kevin F. O'Connell, Ph.D.

NIDDK, National Institutes of Health
Building 8A, Room 2A07
8 Center Dr.
Bethesda, MD 20892
Tel: 301-451-4557
Fax: 301-402-0240

Research Statement:

The centrosome is the cell's primary microtubule-organizing center (MTOC). Through its ability to form a polarized array of microtubules, the centrosome participates in a number of critical cellular processes such as intracellular transport, the generation and maintenance of cellular polarity, cell motility, and cell division. To address questions concerning the function and maintenance of the centrosome, we use the small genetically-tractable nemotode worm Caenorhabditis elegans as a model system. Because the mechanisms under study in C. elegans are likely to be highly conserved, our findings should prove valuable in understanding the analogous processes in humans and how defects in these processes lead to disease.

Centrosome Duplication

Centrosomes are major determinants of mitotic spindle bipolarity. A mitotic cell possesses two centrosomes, each of which establishes one of the spindle poles. During division, the cytokinetic furrow bisects the spindle, ensuring that each daughter cell receives one centrosome. To assemble its own bipolar spindle, each daughter cell must duplicate its centrosome once and only once. Defects in this process can lead to spindle abnormalities, aneuploidy, and ultimately genomic instability, a state associated with cells undergoing neoplastic progression.

We have identified two genes required for centrosome duplication. The zyg-1 gene encodes a protein kinase that localizes to centrosomes in a transient manner. Mutations in this gene lead to embryonic lethality marked by a failure to form bipolar spindles. We have performed an ultrastructural analysis of this defect and found that an important component of the centrosome-the centriole-fails to replicate. Thus, ZYG-1 regulates the critical process of daughter centriole formation. To accomplish this task, ZYG-1 functions together with a second protein encoded by the spd-2 gene. SPD-2 is a coiled-coil protein that also localizes to the centrosome. SPD-2 is required for centrosome duplication and genetically interacts with ZYG-1. The exact nature of the ZYG-1-SPD-2 interaction is not yet known and is currently under investigation in my lab.

Centrosome Maturation

The centrosome is a dynamic organelle, and during the cell cycle, its composition changes dramatically. The change in composition is mirrored by changes in microtubule-nucleating capacity. Microtubule growth is initiated within a region of the centrosome referred to as the pericentriolar material, or PCM. Early in the cell cycle, the centrosome contains only a small amount of PCM and organizes a relatively small number of microtubules. As cells progress toward mitosis, the amount of PCM and the microtubule-nucleating capacity increase, a process termed maturation. Maturation involves the recruitment of PCM components such as g-tubulin from cytoplasmic stores and has been intensively studied in embryonic systems, in which an initially inactive sperm-derived centriole pair must accrue PCM components from the oocyte cytoplasm to become a full-fledged MTOC.

My lab has demonstrated that SPD-2 also functions in the process of maturation. In newly fertilized embryos, SPD-2 gradually accumulates at the centrosome concomitant with an increase in the number of microtubules organized. In embryos lacking SPD-2, the centrosomes accrue only small amounts of PCM, organize relatively few microtubules, and fail to assemble a mitotic spindle. Thus, SPD-2 is an unusual MTOC component in that it is required for the two basic functions of the centrosome-microtubule organization and duplication-a finding that suggests that the processes of duplication and maturation have some mechanistic similarities. Further study of SPD-2 will provide important insight into the molecular mechanisms that underlie these essential processes.

Selected Publications:

Song, M.H., Aravind, L., Müller-Reichert, T., and O'Connell, K.F. (2008). The Conserved Protein SZY-20 Opposes the Plk4-Related Kinase ZYG-1 to Limit Centrosome Size. Dev. Cell 15, 901-912. [Full Text/Abstract]

Song, M.H., Miliaras, N.B., Peel, N., and O'Connell, K.F. (2008). Centrioles: some self-assembly required. Curr Opin Cell Biol. 20, 688-693. [Full Text/Abstract]

Golden A, O'Connell KF. Silence is golden: combining RNAi and live cell imaging to study cell cycle regulatory genes during Caenorhabditis elegans development. Methods(41): 190-197, 2007. [Full Text/Abstract]

Kemp, C. A., Song, M. H, Addepalli, M. K., Hunter, G., O'Connell, K. Suppressors of zyg-1 Define Regulators of Centrosome Duplication and Nuclear Association in Caenorhabditis elegans. Genetics(176): 95-113, 2007. [Full Text/Abstract]

Kemp, C. A., Kopish, K. R., Zipperlen, P., Arhinger, J., and O'Connell, K. F. Centrosome Maturation and Duplication In C. elegans Require the Coiled-Coil Protein SPD-2. Dev. Cell(6): 511-523, 2004.

O'Connell KF The ZYG-1 kinase, a mitotic and meiotic regulator of centriole replication. Oncogene(21): 6201-8, 2002. [Full Text/Abstract]

O'Connell KF Caron C Kopish KR Hurd DD Kemphues KJ Li Y White JG The C. elegans zyg-1 gene encodes a regulator of centrosome duplication with distinct maternal and paternal roles in the embryo. Cell(105): 547-58, 2001. [Full Text/Abstract]

O'Connell KF The centrosome of the early C. elegans embryo: inheritance, assembly, replication, and developmental roles. Curr Top Dev Biol(49): 365-84, 2000. [Full Text/Abstract]

O'Connell KF Maxwell KN White JG The spd-2 gene is required for polarization of the anteroposterior axis and formation of the sperm asters in the Caenorhabditis elegans zygote. Dev Biol(222): 55-70, 2000. [Full Text/Abstract]

O'Connell KF Leys CM White JG A genetic screen for temperature-sensitive cell-division mutants of Caenorhabditis elegansGenetics(149): 1303-21, 1998. [Full Text/Abstract]

Page last updated: December 17, 2008

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