Investigating the impact of centrosome number on neuroepithelial maturation and proliferative compensation

• Applicant: Dr. Caren Norden
• Subject Area: Developmental Biology ; Cell Biology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 310521253

Centrosomes are the major microtubule organizing centres in most animal cells. After cell division, cells contain one centrosome consisting of two centrioles. These are duplicated prior to mitosis resulting in two centrosomes. Errors in the centrosome duplication pathway, leading to the generation of more or less than two centrosomes (centrosome amplification/depletion), can have severe consequences for cell division. Such scenarios therefore have been associated with serious diseases, including microcephaly (small brains) and cancer. However, the full spectrum of in vivo consequences of changes in centrosome numbers for developing organisms is not yet understood. While we and other groups made headway by investigating centrosome amplification in developing flies, mice and zebrafish, many open questions remain. It is for example not fully understood how individual cells react to wrong centrosome numbers and how unaffected tissue responds to apoptotic tissue death.With this proposal we aim to shed further light into the questions how cell biology is altered when cells have the wrong number of centrosomes and how this influences tissue development and maturation. We use the zebrafish retinal neuroepithelium as a model to understand the impact of centrosome duplication errors on early brain development. To achieve this, we will make use of previously established tools in the lab that allow to reproducibly change centrosome numbers at different developmental stages. We want to understand whether and how cell cycle dynamics change and how this differs in different centrosome amplification scenarios. We will also investigate in which conditions centrosome amplification leads to cell death and how and when this is triggered. As we already know that cells inheriting the wrong assortment of genetic material do not always die, an important question to answer will be how cells manage aneuploidy conditions and to what extend and how aneuploidy can be tolerated.Another focus of our interest is how remaining or introduced wild type cells in the tissue counteract apoptotic phenotypes induced by centrosome amplification. This is a process called compensatory proliferation that has not yet been extensively studied in vertebrate systems. We want to understand and evaluate the basic parameters that induce compensatory proliferation and their limitations. We will investigate whether and how cell cycle dynamics of compensating cells change and how this influences compensation scenarios. Further, we will explore how compensation is switched off, once the damage tissue has been restored. Overall, we expect to gather unmatched insights into how cells and tissues react to changes in centrosome number. We will further evaluate the capabilities of the neuroepithelium to rescue developmental programs in stress situations like the massive induction of cell death.

• DFG Programme: Research Grants