Principal Investigator – Junior Research Group Leader, CECAD Cologne
Dr. Hisham Bazzi
The Bazzi laboratory is investigating the roles of cytoskeletal organizers in mammalian development and homeostasis. Dr. Bazzi and his team are focusing on the functions of centrosomes in the developing mouse and in stem cells. They use mouse genetics to study the consequences of the loss of centrosomes on various cell processes such as cell cycle, division, polarity, migration, signaling and fate determination. The lab’s goal is to shed light on centrosome-related human diseases and to help find ways of treating them.
Our research: The Bazzi laboratory studies centrosome function in stem cells. The team aims to define the function of centrosomes in asymmetric stem cell divisions in the developing and regenerative skin stem cells. To this end, they use mouse genetic approaches in vivo for the conditional removal of the centrosome, and investigate the consequences and the corresponding mechanisms.
Our successes: Using genetic mutations in the mouse, the team has removed centrosome function in the developing mouse embryo and brain. Activation of a p53-dependent apoptosis pathway was a major outcome in both systems. This as yet uncharacterized pathway is independent of DNA damage or abnormalities in chromosome segregation. The Bazzi group is currently working to unravel this novel mechanism.
Our goals: Although several functions have been proposed for the centrosome in animal cells, it is now widely accepted that the centrosome is essential to provide a template for cilia and flagella in resting cells, and helps organize the mitotic spindle during cell division. The Bazzi group is working to determine the tissue- and cell-specific functions of centrosomes. For example, they have shown that centrosomes are required to anchor the highly proliferative neuronal progenitors at their niche in the brain. They aim to use stem cells and the skin models to uncover more developmental and adult functions of centrosomes.
Our methods/techniques: The Bazzi laboratory primarily uses mouse genetic approaches to address the functions of centrosomes and other cytoskeletal organizers. They also resort to primary cell cultures to examine the mechanisms that prove difficult to solve in the mouse. The team uses a variety of common molecular, cell biology, and biochemical techniques to build biological pathways. They are also using modern techniques of gene targeting such as the CRISPR/Cas9 system and global approaches including mass spectrometry and RNA-Seq.
Figure 1: The loss of centrosomes, through the knockout of a gene called Sas-4, results in massive cell death leading to a highly dysmorphic dead mouse embryo on embryonic day (E) 9.5. Rescue from cell death, through the simultaneous removal of p53 and Sas-4, results in healthier embryos that still lack cilia. The double mutants show the typical exencephaly and randomized heart looping that are characteristic of cilia mutants. (Adapted from Bazzi and Anderson, 2014).
Figure 2: The loss of centrosomes in the neural cortex, through the conditional removal of Sas-4, results in the detachment of radial glial progenitors (RGPs), marked by PAX6, from their normal niche in the ventricular zone (VZ) on E15.5. The detaching RGPs are lost through p53-dependent cell death. Similar to the mouse embryo, RGPs are rescued when p53 is also removed and remain proliferative in the deeper layers of the cortex. (Adapted from Insolera*, Bazzi* et al, 2014).