Dr. Tang, Tang K. 唐堂 博士
Ph.D. Human Genetics, Yale University
Centrioles/Centrosomes, Cilia, Neural Stem Cells, and Tumorigenesis
Centrioles are essential components of the centrosomes, which are required for the formation of the mitotic spindles, cilia, and flagella. Centriole duplication involves the growth of a procentriole (daughter centriole) from an existing centriole (mother centriole). Primary microcephaly (MCPH) is characterized by a substantial reduction in size of the cerebral cortex with mild to severe mental retardation. Recently, mutations in many centriolar genes have been reported to cause MCPH and ciliopathies, but their underlining mechanisms remain incompletely understood. During the past years, my lab has identified several key proteins that participate in centriole duplication and cilia formation. We found that CPAP cooperates with CEP120 to regulate centriole length (Nat Cell Biol. 2009; J Cell Biol 2013; Sci Rep 2019). We further demonstrated that CPAP and STIL could interact with each other (EMBO J, 2011) and form complexes with CEP135 (EMBO J, 2013), CEP120 (J Cell Biol, 2013), and RTTN (Nat Commun, 2017), and such interactions are critical to build a full-length centriole. Interestingly, mutations in CPAP, STIL, CEP135, and RTTN genes cause primary microcephaly, and complete loss of CPAP produces severe and neurological phenotypes in developing mouse brain (J Cell Sci, 2020). Our findings support a concept that defect in centriole biogenesis is one of main causes for MCPH. In addition, we also found that Myosin-Va mediates the initial transportation of preciliary vesicles to the mother centriole, that defines the onset of ciliogenesis (Nat Cell Biol 2018). Recent reports showed that uncontrolled centriole/centrosome replication might lead to unrestrained proliferation and chromosome instability in cancers. We will use a combination of molecular and cellular, genetic, animal model, and hiPSC-derived organoid approaches to understand how the cellular organelles (centrioles or cilia) are established and how mutations in centriolar genes cause primary microcephaly, ciliopathies, and tumorigenesis in humans.
中心粒/中心體，纖毛，神經幹細胞，與癌細胞分裂之研究
細胞中心體含有母、子二顆中心粒，主要是促成細胞纖毛，鞭毛的形成及參與細胞有絲分裂。畸型小頭症（MCPH）是一種人類遺傳疾病，主要症狀是病人腦容量小，並伴隨中，重度智力障礙。目前已知多個MCPH基因缺陷會造成畸型小頭症。近年來本研究室解開其中4個畸型小頭症蛋白CPAP, STIL, CEP135, 和RTTN的功能。本研究室發現STIL（EMBO J, 2011)， CEP135 (EMBO J, 2013) 都會與CPAP蛋白（Nat Cell Biol 2009）結合，且RTTN亦會與STIL結合（Nat Commun 2017, Cells 2021），形成多個蛋白質複合體，共同參與中心粒的複製與細胞分裂。有趣的是CPAP蛋白缺失會誘發神經幹細胞死亡，神經細胞過早分化，及嚴重腦部病變 （J Cell Sci 2020）。據此我們提出一個假設：干擾細胞中心粒複製，將會抑制神經幹細胞分裂與減少大腦皮層神經細胞數目，繼而造成人類畸型小頭症。另外本研究室亦發現CEP120 (J Cell Biol, 2013; Sci Rep, 2019)與CEP295 (J Cell Sci 2016)蛋白會調控中心粒長度，且Myosin-Va在纖毛起始過程中扮演一非常重要的角色：Myosin-Va會將preciliary vesicles首先帶到母中心粒上，繼而開啟了纖毛形成初始機轉(Nat Cell Biol 2018)。近年來癌細胞發現有基因體不穩定現象，此有可能是中心體複製不正常所致。未來本研究室將利用分子，細胞，遺傳，小鼠模式，及hiPSC-derived類人腦器官之技術來探討中心體/中心粒及纖毛形成機轉，並探討干擾此機轉所可能誘發人類畸型小頭症，纖毛病變，及癌基因體不穩定之病因。
