TY - JOUR
T1 - The Mammalian SPD-2 Ortholog Cep192 Regulates Centrosome Biogenesis
AU - Zhu, Fei
AU - Lawo, Steffen
AU - Bird, Alex
AU - Pinchev, Deborah
AU - Ralph, Alison
AU - Richter, Constance
AU - Müller-Reichert, Thomas
AU - Kittler, Ralf
AU - Hyman, Anthony A.
AU - Pelletier, Laurence
N1 - Funding Information:
We would like to thank Andreas Merdes and Jeffrey Salisbury for their kind gift of NEDD-1 and Centrin antibodies, Michel Bornens for the Centrin-GFP line, Anne Grabner from Cenix Bioscience for preliminary work on Cep192, Erich Nigg and Christopher Wilkinson for sharing unpublished results, Mike Tipsword, Martine Ruer, and David Drechsel for antibody production, Frank Buchholz, Ina Poser, and Martina Augsburg for help with BAC transgenesis, Andrea Tagliaferro for esiRNA production, Robert Temkin and Doug Holmyard at the Advanced Bioimaging Centre at the Mount Sinai Hospital for immuno-EM, Jana Mäntler for excellent technical assistance with thin-section EM, Kate Fairbrother for help with image analysis, and Daniel Durocher and Friederike Quittnat Pelletier for critical comments on this manuscript. During the course of this work, A.B. and R.K. were supported by the Human Frontier Science Program, A.A.H. by the Max Planck Society and the European Union Mitocheck consortium, and L.P. by the Human Frontier Science Program and the Samuel Lunenfeld Research Institute.
PY - 2008/1/22
Y1 - 2008/1/22
N2 - Centrosomes are the major microtubule-organizing centers of mammalian cells. They are composed of a centriole pair and surrounding microtubule-nucleating material termed pericentriolar material (PCM) [1]. Bipolar mitotic spindle assembly relies on two intertwined processes: centriole duplication and centrosome maturation. In the first process, the single interphase centrosome duplicates in a tightly regulated manner so that two centrosomes are present in mitosis [2, 3]. In the second process, the two centrosomes increase in size and microtubule nucleation capacity through PCM recruitment, a process referred to as centrosome maturation [4]. Failure to properly orchestrate centrosome duplication and maturation is inevitably linked to spindle defects, which can result in aneuploidy and promote cancer progression [5]. It has been proposed that centriole assembly during duplication relies on both PCM and centriole proteins, raising the possibility that centriole duplication depends on PCM recruitment [6]. In support of this model, C. elegans SPD-2 and mammalian NEDD-1 (GCP-WD) are key regulators of both these processes [7-13]. SPD-2 protein sequence homologs have been identified in flies, mice, and humans, but their roles in centrosome biogenesis until now have remained unclear [10, 14-16]. Here, we show that Cep192, the human homolog of C. elegans and D. melanogaster SPD-2, is a major regulator of PCM recruitment, centrosome maturation, and centriole duplication in mammalian cells. We propose a model in which Cep192 and Pericentrin are mutually dependent for their localization to mitotic centrosomes during centrosome maturation. Both proteins are then required for NEDD-1 recruitment and the subsequent assembly of γ-TuRCs and other factors into fully functional centrosomes.
AB - Centrosomes are the major microtubule-organizing centers of mammalian cells. They are composed of a centriole pair and surrounding microtubule-nucleating material termed pericentriolar material (PCM) [1]. Bipolar mitotic spindle assembly relies on two intertwined processes: centriole duplication and centrosome maturation. In the first process, the single interphase centrosome duplicates in a tightly regulated manner so that two centrosomes are present in mitosis [2, 3]. In the second process, the two centrosomes increase in size and microtubule nucleation capacity through PCM recruitment, a process referred to as centrosome maturation [4]. Failure to properly orchestrate centrosome duplication and maturation is inevitably linked to spindle defects, which can result in aneuploidy and promote cancer progression [5]. It has been proposed that centriole assembly during duplication relies on both PCM and centriole proteins, raising the possibility that centriole duplication depends on PCM recruitment [6]. In support of this model, C. elegans SPD-2 and mammalian NEDD-1 (GCP-WD) are key regulators of both these processes [7-13]. SPD-2 protein sequence homologs have been identified in flies, mice, and humans, but their roles in centrosome biogenesis until now have remained unclear [10, 14-16]. Here, we show that Cep192, the human homolog of C. elegans and D. melanogaster SPD-2, is a major regulator of PCM recruitment, centrosome maturation, and centriole duplication in mammalian cells. We propose a model in which Cep192 and Pericentrin are mutually dependent for their localization to mitotic centrosomes during centrosome maturation. Both proteins are then required for NEDD-1 recruitment and the subsequent assembly of γ-TuRCs and other factors into fully functional centrosomes.
KW - CELLBIO
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=38349050936&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38349050936&partnerID=8YFLogxK
U2 - 10.1016/j.cub.2007.12.055
DO - 10.1016/j.cub.2007.12.055
M3 - Article
C2 - 18207742
AN - SCOPUS:38349050936
SN - 0960-9822
VL - 18
SP - 136
EP - 141
JO - Current Biology
JF - Current Biology
IS - 2
ER -