In a research article published in the August issue of the prestigious scientific journal Nature Communications, Dr. Tang K. Tang, a Distinguished Research Fellow at the Institute of Biomedical Sciences (IBMS), Academia Sinica, and Dr. Won-Jing Wang from National Yang-Ming University uncovers for the first time the role of a previously uncharacterized microcephaly protein RTTN during centriole duplication.
Cell division in higher animals includes DNA replication and centriole duplication. The major molecular details of DNA replication have been elucidated, but the molecular mechanisms underlying centriole duplication in human cells are incompletely understood. Centrosomes are the major microtubule organizing centers (MTOCs) in mammalian cells. Each centrosome is composed of two orthogonal cylindrical microtubule-based structures, called centrioles, which are surrounded by an electron-dense pericentriolar matrix (PCM). The centrosome is essential for the assembly of mitotic microtubules, which are required for accurate chromosome segregation during mitosis.
Centriole duplication cycle can be subdivided into three steps: Initiation, elongation, and maturation. The importance of this Nature Communications paper is to reveal the molecular mechanism of how RTTN regulates centriole duplication, particularly in the step of centriole elongation. The research team found that RTTN interacts with another microcephaly protein STIL and regulates centriole assembly. STIL is involved in the initiation step, while RTTN plays a role in the latter elongation step of centriole assembly. Depletion of RTTN inhibits the loading of POC1B and POC5 to the distal-half centrioles resulted in producing shorter centrioles. Interestingly, the naturally occurring microcephaly-associated mutant (RTTN-A578P) shows a low affinity for STIL binding and blocks centriole assembly. These findings suggest that RTTN contributes to building full-length centrioles and the RTTN-A578P mutant which causes defects in centriole duplication may possibly induce neural cell death in primary microcephaly (MCPH) patients.
MCPH is a neurodevelopmental genetic disorder, characterized by a substantial reduction in size of the cerebral cortex with mild to severe mental retardation. Recent studies from many laboratories have reported that mutations in the CPAP/CENPJ, STIL, CEP135, and RTTN genes cause MCPH, but the molecular details were not elucidated. During past years, Dr. Tang’s laboratory has identified the key roles of four human microcephaly proteins, CPAP, STIL, CEP135, and RTTN, involved in centriole duplication. Dr. Tang’s lab found that CPAP regulates centriole elongation (Nat. Cell Biol. 2009). His lab further demonstrated that various human microcephaly proteins could form separate complexes, including CPAP-STIL (EMBO J. 2011), CPAP-SAS6-CEP135 (EMBO J. 2013), and RTTN-STIL (Nat. Commun. 2017), which are required to build a full-length centriole during centriole duplication. This led to the design of a molecular mechanistic model, which describes how these four microcephaly proteins participate in centriole duplication. This finding also leads to hypothesize that defects in centriole duplication in neural progenitor cells may cause neural cell death and reduce brain size in MCPH patients.
The authors of this paper: Hsin-Yi Chen, Chien-Ting Wu, Chieh-Ju C. Tang, Yi-Nan Lin, Won-Jing Wang, and Tang K. Tang.
Dr. Tang K. Tang, Institute of Biomedical Sciences, Academia Sinica
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