Microtubule Nucleation: Structure & Mechanism

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Investigator: David A. Agard, PhD
Sponsor: NIH National Institute of General Medical Sciences

Location(s): United States

Description

The centrosome is of fundamental importance to animal cells in that it is the principal nucleator of the microtubule (MT) cytoskeleton and harbors the centrioles, specialized structures that are required for cilia formation and contribute to spindle-pole positioning. Through these principal roles, the centrosome is important in embryonic development and human disease. During interphase, MTs are required for vesicle trafficking and cell polarity. In most cell types, many of the MTs that form the mitotic spindle originate at the centrosome. The centrosome also has important roles beyond MT nucleation, including functions in cytokinesis, progression through the cell cycle, and in sequestering or positioning some proteins to control when and where they are active. The primary aims of this proposal are to determine the molecular mechanism of MT nucleation, and to understand how the nucleating machinery is assembled and regulated. The proposed experiments will continue and expand upon these results, providing a detailed understanding of the physical origins of MT assembly, and the cellular machinery that dictates MT formation. In vitro predictions of modes of action or regulation will be assayed in vivo using mutagenesis and siRNA and live imaging. The normal function of centrosomes and centrioles is directly relevant to human disease, and the proposed work is aimed at understanding the molecular mechanisms of these cellular components. Abnormal centrosome number and behavior is a common hallmark of cancer cells, and centriole defects are involved in many human ciliary diseases, including nephronophthisis, Bardet-Biedl syndrome, Meckel syndrome, and Oral-Facial-Digital syndrome. The normal function of centrosomes and centrioles is directly relevant to human disease, and the proposed work is aimed at understanding the molecular mechanisms of these cellular components. Abnormal centrosome number and behavior is a common hallmark of cancer cells, and centriole defects are involved in many human ciliary diseases, including nephronophthisis, Bardet-Biedl syndrome, Meckel syndrome, and Oral-Facial-Digital syndrome.