First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Maayan Barnea-Zohar and Sabina E. Winograd-Katz are co-first authors on ‘ An SNX10-dependent mechanism downregulates fusion between mature osteoclasts’, published in JCS. Maayan is a research assistant in the lab of Ari Elson at the Weizmann Institute of Science, Rehovot, Israel, investigating cell–cell fusion in osteoclasts and how cell size is determined. Sabina is a research assistant and lab manager in the lab of Benjamin Geiger at the Weizmann Institute of Science, investigating cell biology and signaling.

Maayan Barnea-Zohar and Sabina E. Winograd-Katz

How would you explain the main findings of your paper in lay terms?

M.B.-Z. and S.E.W.-K.: Osteoclasts, bone-resorbing cells, are large cells with many nuclei that are formed by fusion of many macrophages, a type of white blood cell of the immune system. The details of this fusion process, and especially what stops it when the fused cell reaches its appropriate size, are not understood. In our study, we investigated osteoclast size determination in mice carrying a mutation in a protein called SNX10. This mutation is known to induce osteopetrosis, a rare and often lethal genetic disorder that is caused by the failure of osteoclast-mediated bone resorption, both in humans and in mice. When we initially analysed osteoclasts from mice carrying the mutation, we found that the cells fused uncontrollably, forming giant dysfunctional osteoclasts that could become 10–100-fold larger than their wild-type counterparts. We now use this model to better understand what determines cell size and which mechanisms are involved in this process.

Were there any specific challenges associated with this project? If so, how did you overcome them?

M.B.-Z.: Osteoclasts are a very delicate cellular model that presents challenges of different types. One such challenge arises from the biology of these cells, especially when trying to perform overexpression and rescue experiments. Most of the systems that are used to introduce foreign DNA to cells via transfection rely on the ability of a cell to divide, whereas osteoclasts fuse. I tried different systems for 2 years until we finally decided to work with adenovirus, which enabled us to visualize protein localization and perform rescue experiments.

S.E.W.-K.: One of the most challenging issues was to find the right conditions to observe the osteoclastogenesis of wild-type and mutant osteoclasts at the same time. This was not trivial, since the mutants were always much faster growing than the wild type. Later, we found that growing the cells and reseeding the same number of precursors after growing them with MCSF was the solution.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

S.E.W.-K.: My ‘eureka’ moment for this research project was when I first saw the montage movie of SNX10-mutant osteoclasts undergoing fusion. It was amazing! Although we were aware of the phenotype from still images, the movie showed the amazing difference in fusion. I then understood that we were dealing with a central regulator of the fusion process.

M.B.-Z.: A striking moment for me was seeing that even a very small number of wild-type healthy cells mixed with mutant cells recovered some resorption activity. I really did not expect to see any activity when almost 90% of the cells were carrying the mutation and did not look much different from the 100% mutant cells. Seeing the pits in the bone, although shallow and smaller, was an interesting revelation.

Why did you choose Journal of Cell Science for your paper?

M.B.-Z.: We were looking for a journal with a wide scope in the field of cell biology. Osteoclasts are usually represented as a narrow niche in bone biology research, but we think that this research has wider implications for the field. Since Journal of Cell Science publishes a full range of topics in cell biology, we found it to be a good platform to bring the finding to the cell biology research community.

S.E.W.-K.: Since I started research in the field of cell biology, I have read many articles in Journal of Cell Science. I think the journal was the best fit for our research, combining the possibility of showing our microscopy data together with the cellular mechanisms. Many of the lab's research achievements have been published in the journal before, including one project in which I was involved.

Spleen-derived osteoclasts from wild-type (WT) and R51Q-SNX10-mutant mice grown on glass coverslips andstained for actin (red), tubulin (green) and DNA (blue). Each image is a composite of 12 smaller fields. Scale bars: 200 µm.

Spleen-derived osteoclasts from wild-type (WT) and R51Q-SNX10-mutant mice grown on glass coverslips andstained for actin (red), tubulin (green) and DNA (blue). Each image is a composite of 12 smaller fields. Scale bars: 200 µm.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

S.E.W.-K.: The research presented here is part of a bigger initiative that involves a very interesting collaboration between labs in Germany, Israel and Palestine. We have met a few times in Germany and in Israel. Sharing information and brainstorming with researchers coming from different fields and different cultural backgrounds was very special and enlightening.

M.B.-Z.: Indeed, this project is quite unique in the way it is conducted. While most of the projects around us are usually carried out in one laboratory, and sometimes a PhD student gets to have a second supervising mentor, here the research was entwined and resulted in a nice collaboration across labs and even countries. Although most of my day-to-day work was carried out in Professor Elson's laboratory, the periodical meetings with Professors Geiger, Kanaan and Tuckermann resulted in very interesting insights. Watching them discussing both research and even the mundane administrative work involved in such a collaboration was very educational.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

M.B.-Z.: As a young girl, I dreamed of becoming a physician and loved biology in particular. When I grew up, circumstances led to me completing a bachelor's degree in hotel management, but my love for biology was never abandoned. At some point in my short-lived career outside of the academy, I realized that I really wanted to go back to studying science. It was challenging, since I lacked a lot of background, but once I was in the lab, I knew it was my place. Since then, I have never wanted to leave.

S.E.W.-K.: I was always eager to learn things about nature. Near the end of secondary school, I heard a lecture about oncogenes and tumor suppressor genes; I was fascinated and decided to study biology. In every new field of study, I've always wanted to know more about mechanisms – how things happen and how they are regulated.

Who are your role models in science? Why?

S.E.W.-K.: I admire many researchers that I've interacted with during my career. I take something from each and every one of them. I love out-of-the-box thinking. I like scientists that like to share and collaborate, and I also respect most the scientists that have a good work–family balance. I think Professor Geiger, who I have worked with for many years, is one of the best role models for all of these reasons.

M.B.-Z.: Professor Elson. I have been working with him for almost 7 years now, beginning as a postdoctoral fellow and then as a research assistant. I admire his integrity, diligence and dedication to doing good science. He loves teaching, which is very important whenever there is a new student, and although he has been the principal investigator of a lab for many years, he has never stopped doing some of the experiments himself.

What's next for you?

S.E.W.-K.: As a researcher and lab manager, I am very happy. This job offers the possibility to be involved in many different research projects as well as in other aspects of science. I hope I will continue doing research and helping others doing research for many more years.

M.B.-Z.: Due to some personal circumstances a few years ago, I had to relinquish my dream of establishing my own lab as a principal investigator. I replaced it with the hope to become a research fellow in the future, maybe helping a young scientist with the experience I was fortunate to gain. I cannot think of leaving academia.

Tell us something interesting about yourself that wouldn't be on your CV

S.E.W.-K.: I love running and hiking. I think that, like in research, you have an aim, but you need to enjoy the way.

M.B.-Z.: Three years ago, my daughter asked to learn how to crochet. At the time, I did not know even the most basic stitches, so I had to learn from online movies. Since then, my daughter forgot her request, but I became an enthusiast crocheter, learning more and more techniques.

Maayan Barnea-Zohar and Sabina E. Winograd-Katz's contact details: The Weizmann Institute of Science, Rehovot 76100, Israel.

E-mail: [email protected]; [email protected]

Barnea-Zohar
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Shalev
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Stein
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2021
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An SNX10-dependent mechanism downregulates fusion between mature osteoclasts
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J. Cell Sci.
134
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jcs254979
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