Heads of Laboratories
During mitosis, a full set of chromosomes must be equally distributed to the offspring of each dividing cell, and failure to do so can result in numerous disorders, including birth defects and tumor progression. The Funabiki lab studies how chromosomes signal to spatially and temporally orchestrate a precise series of mitotic events to ensure accurate chromosome segregation.
A mitotic cell undergoes a series of dramatic morphological changes, including chromosome condensation, spindle formation, chromosome segregation and cytokinesis. These events must occur at the right place, at the right time, in the right order. In particular, the Funabiki lab studies the following subjects.
Spatial control of chromosome-induced signals during mitosis. The Funabiki lab has demonstrated that mitosis-specific phosphorylation of histone H3, the major component of chromosomes, plays a key role in formation of the spindle, a cellular apparatus to segregate chromosomes. They have shown that Survivin, whose expression is implicated in cancer development, binds histone H3 that is phosphorylated at the threonine 3 residue (H3T3ph). This binding results in recruitment and activation of the kinase Aurora B, which leads to spindle assembly around chromosomes. At the end of mitosis, chromosomes must stop supporting the spindle assembly and initiate nuclear envelope assembly. This dramatic conversion of chromosome-assisted intracellular architecture is mediated in part by silencing the Aurora B activity on chromosomes. However, the nuclear envelope should not reform before completion of chromosome segregation, and thus the timing of this conversion must be accurately controlled. The Funabiki lab has shown that dephosphorylation of H3T3ph plays a key role in this process, and they are now studying how the activity of H3T3 kinase, Haspin, is regulated during the cell cycle. Furthermore, they have identified a novel chromatin-associated regulator of microtubule dynamics, which plays a critical role in controlling the proper size and shape of the nucleus. Through these studies, Dr. Funabiki aims to understand the mechanisms by which the precise order of events during mitosis is controlled by chromatin-induced signals.
Mechanical control that transduces microtubule attachment into the chemical signal to permit chromosome separation. In order to segregate chromosomes, microtubules must attach to the proteinaceous structure, the kinetochore, which is built on each centromere of chromosomes. Importantly, until all the kinetochores attach to microtubules in the right orientation, unattached kinetochores activate a signaling pathway called the “spindle assembly checkpoint” to delay sister chromatid separation and exit from mitosis. Collaborating with Rockefeller’s Fred Cross, Dr. Funabiki discovered that the protein phosphatase 1 at the kinetochore is critical for silencing the checkpoint upon microtubule attachment. They aim to understand the mechanism by which phosphatase converts the microtubule attachment event into checkpoint silencing. In addition, using superresolution microscopy, they are studying how the three-dimensional architecture of the kinetochore is modulated by microtubule attachment status.
Roles of histone modifications during mitosis. Upon entry into mitosis, chromosomes show dramatic structural changes accompanied with histone phosphorylation. The functional significance of mitotic histone phosphorylation remains largely unclear. The Funabiki lab aims to develop a method to examine the role of histone modification using frog egg extracts.
Mechanisms that control the integrity of the centromeric repetitive DNA. The human centromere is composed of highly ordered repeats of alpha-satellite DNA. The Funabiki lab studies the molecular mechanisms that maintain size and order and the centromere’s relevance to cancers.
Dr. Funabiki received his bachelor’s degree in chemistry in 1990 and his Ph.D. in cell biology in 1995, both from Kyoto University in Japan. From 1996 until 2000 he worked as a postdoc in the physiology department at the University of California, San Francisco, and then at Harvard University as a postdoc in molecular and cellular biology. He came to Rockefeller as assistant professor and head of the Laboratory of Chromosome and Cell Biology in 2002 and was promoted to associate professor in 2007.
Dr. Funabiki received the Alexandrine and Alexander L. Sinsheimer Fund Scholar Award and the Irma T. Hirschl/Monique Weill-Caulier Trust Research Award in 2003. He received the Searle Scholar Award from the Chicago Community Trust in 2002. He was a special fellow of the Leukemia and Lymphoma Society from 1999 to 2002 and a Leukemia and Lymphoma Society fellow from 1996 to 1999.
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