How a unique mouse sheds light on the Notch signaling pathway – PhD Defense Yasmine el Azhar

Signals within cells play a crucial role in embryonic development and maintaining healthy tissues. These signals act like messengers, delivering information to cells via molecules. The message helps a cell determine whether it should grow, specialize, or be removed. The signaling pathway starts when receptors on the cell’s surface detect specific molecules, like antennas. These signals are then relayed to other parts of the cell, where they can activate or suppress genes. If a signaling pathway malfunctions, diseases such as developmental disorders or cancer can arise. By understanding how these signals work, researchers can develop new treatments.

The role of the Notch signaling pathway in cellular decisions

Cells receive and process signals through feedback systems. This enables cells to adjust the strength and timing of signals as needed. Feedback systems can create oscillations, or rhythmic fluctuations in signal intensity. Such oscillations help cells to fine-tune cellular responses. The Notch signaling pathway plays a significant role in these processes. This pathway determines how cells develop, divide, and grow. The Notch protein regulates other proteins, such as the transcription factor Hes1. Disruptions in the Notch signaling pathway can lead to uncontrolled cell growth, contributing to diseases like cancer. By studying pathways like Notch, researchers can uncover insights into disease mechanisms and treatments.

A fluorescent mouse model for signaling studies  

To investigate the role of the Notch protein in embryonic development and tissue maintenance, El Azhar studied the Notch signaling pathway by looking at Hes1 oscillations. She developed a unique type of mouse in which each Hes1 protein was linked to a fluorescent protein. This research model, in which mice were used to study biological processes, was a cornerstone of her PhD research. Thanks to this mouse model, El Azhar and her colleagues were able to to track Hes1 protein oscillations in real time in live cells from various tissues. “We confirmed that Notch signaling is primarily responsible for regulating Hes1 in the tail of a mouse embryo, providing new insights into how stem cells form tissues,” El Azhar explains.

Dynamics of Hes1 during embryonic development

El Azhar studied Hes1 oscillations in different cell types during embryonic development. She focused on cells in the presomitic mesoderm, a region in the embryo where cells prepare to form tissues like muscles and bones. In these cells, Hes1 oscillations were strong and well-coordinated. In the preneural tube, an early stage of the nervous system, the oscillations were weaker and less regular. These differences in rhythm were critical for cell growth and development in these areas. “We found that when we inhibited the Notch protein, Hes1 oscillations almost disappeared in the presomitic mesoderm. This was not the case in the preneural tube.” says El Azhar. These results demonstrate that Notch signaling affects Hes1 differently depending on the cell type.

Feedback and Resilience

Throughout her PhD journey, El Azhar discovered the importance of feedback, not only for cell functioning, but also for the functioning of a researcher. Positive responses from experts at international conferences gave her insights into the value of her findings. She encourages other researchers to build support networks and seek help when needed. “This helps you maintain perspective and find courage. Remember, asking for help and taking breaks are important parts of the job,” she advises. El Azhar also emphasizes the value of soft skills and resilience. “Identify which parts of your work energize you, and find ways to make less enjoyable tasks more pleasant. Also, prioritize activities you enjoy in your free time and make room for them outside work hours.”