How does a human cell control formation of primary cilia at molecular level?

Primary cilium Primary cilia are antenna–like organelles present on surface of most cells. Even though they were discovered many decades ago, they were for a long time pretty much neglected and even considered vestigial. That has very much changed during last 10 years or so, when the importance of primary cilia for cell communications, correct embryo development, and tissue homeostasis in adulthood have started to be appreciated, together with revealed connections between primary cilia defects and a number of diseases called ciliopathies.

Our aim in this project to understand how a cell controls formation of primary cilia. Specifically, we are focusing on the role of a protein called Tau tubulin kinase 2 (TTBK2), which acts as a key regulatory element (“switch”) of a cell program to make a cilium. Previous work from both us and others showed that TTBK2 has to be present in a cell at the right time and at the right place - than it can trigger the program of cilium making. When it is absent the cilium cannot be made. In addition, mutations in TTBK2 gene can lead to a disease, which further underscores that fully functional TTBK2 is very important. Based on these facts the key question we are asking here is how is TTBK2 doing it? What actually makes it important? To tackle this question, we are using various approaches, including proteomics, gene editing, high resolution microscopy, and biochemistry.

What are consequences of centriole abnormalities for stem cells and their differentiated progeny?

Cancer, primary microcephaly and primordial dwarfisms – these are examples of diseases so different and yet sharing some similarities – the common link between those are abnormalities in the number of centrioles - barrel shaped organelles important for cell division (forming the core of centrosome) and cell to cell communication (forming the base of primary cilia).

Centrioles Currently it is not clear how exactly does abnormal centriole number contribute to development of the above mentioned diseases – why in some situations centriole abnormalities seem to contribute to cancer progression (associated with increased proliferation and/or growth) and in other cases to microcephaly or even dwarfism (both associated with decreased proliferation and/or growth). Our overall aim is to develop a cell based model system that will allow us to study potentially contradictory effects and consequences of centriole abnormalities in different situations. We are currently taking advantage of human embryonic stem cells (hESCs) to achieve this goal.