In their recent Development paper, published in our Immune Special Issue, Manisha Goyal, Tina Mukherjee, and colleagues examine the pathways controlling ROS homeostasis during hematopoietic growth control. They identify an important role for odor-sensing and the GABA pathway in myeloid ROS regulation, which has downstream effects on hematopoietic growth. Now, Manisha gives us some insights into the story behind the paper.
What was already known about the topic?
Dr. Mukherjee’s past work shows the importance of olfaction and GABA signaling in blood-progenitor maintenance (Shim et al., 2013). This work always intrigued me and also motivated me to join the lab. I was fortunate to work on another interesting and fascinating work where we show that olfaction-derived GABA catabolism in blood-progenitor cells regulates their immune response to parasitic wasp infections (Madhwal et al., 2020). Knowing the importance of GABA signaling in blood-progenitor homeostasis and the role of GABA catabolism in immune response, we asked about the involvement of this pathway in homeostatic conditions as well.
How did you get started on this project?
The project started with the observation that perturbation of the GABA catabolic pathway in blood-progenitor cells leads to lymph gland growth retardation. Conversely, we found that perturbation of TCA cycle enzymes in blood-progenitor cells doesn’t affect lymph gland growth in homeostasis. This made us curious to begin exploring the role of GABA catabolism and the TCA cycle in blood-progenitor homeostasis.
What was the key experiment?
There has always been an excitement to do the experiments and analyze the results. The findings that GABA catabolism regulates TCA cycle activity and this regulation is specifically acting on phosphorylation of pyruvate dehydrogenase kinase and not on the total enzyme levels were really fascinating to me. This finding was one of the key experiments connecting GABA catabolism, reactive oxygen species (ROS), and TCA cycle regulation. Moreover, working with fruit flies has always been fun and the tiny flies have made exploring the mechanism of complex pathways simple.
When doing the research, did you have any particular result or eureka moment that has stuck with you?
We had some interesting discussions about our results showing that treatment with an antioxidant (N-acetyl cysteine) was sufficient to rescue the lymph gland growth defect and high ROS levels in larvae with a perturbation in the GABA catabolic pathway in blood-progenitor cells (domeMeso>GatRNAi and domeMeso>SsadhRNAi). This experiment was a turning point for the story where we were able to find an independent role/effect of ROS regulation on lymph gland growth and could take the story further.
And what about the flipside: any moments of frustration or despair?
COVID-19 limited the time we could spend in the lab and there were also other constraints on us, labs, and support workers, which heightened the pressure to work. But the excitement to do the experiments and finding the answers helped us to overcome our frustrations.
Where will this story take the lab?
Currently, we are exploring this research further to unravel another aspect of ROS regulation in blood-progenitor cells. This work bridges GABA catabolism and TCA cycle in blood-progenitor cells and given that ROS homeostasis and TCA cycle are regulated by odor-sensing, we are curious to investigate the mechanism and key metabolic changes in homeostasis, as well as in immune response conditions. Hopefully, we will see the outcomes of the work soon.
What is next for you after this paper?
I continue to be a part of this work and I am exploring other mechanisms of ROS regulation by GABA catabolism.
- Shim, J., Mukherjee, T., Mondal, B. C., Liu, T., Young, G. C., Wijewarnasuriya, D. P., & Banerjee, U. (2013). Olfactory control of blood progenitor maintenance. Cell, 155(5), 1141–1153. https://doi.org/10.1016/j.cell.2013.10.032
- Madhwal, S., Shin, M., Kapoor, A., Goyal, M., Joshi, M. K., Ur Rehman, P. M., Gor, K., Shim, J., & Mukherjee, T. (2020). Metabolic control of cellular immune-competency by odors in Drosophila. eLife, 9, e60376. https://doi.org/10.7554/eLife.60376