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Dr Marisa Merino
Applications accepted all year round
Self-Funded PhD Students Only
Liverpool
United Kingdom
Biochemistry
Biophysics
Cancer Biology
Cell Biology
Developmental Biology
Genetics
Molecular Biology
Molecular Genetics
Structural Biology
About the Project
Morphogen gradient scaling is one of the hottest fields in developmental biology at the moment. Scaling is fundamental, explaining how the machinery that controls pattern formation in development (the morphogens) can adapt, so that organs of different sizes show morphological structures which are proportioned. The same developmental machinery can build the leg of a mouse, an elephant or a tumour.
Living systems compete with each other on the basis of available resources, mating or space. It's not surprising that, within the living individual, the basic functional units of life - the cells - share these competitive attributes1. Cells compete for survival factors, space and also compare fitness traits to win the race of subsistence1-3. Cell Competition was found in Drosophila, where the so-called unfit cells were eliminated from the organ when confronted to the so-called fit cells4. Nowadays, we know that there are several mutations triggering these “battles”, where the 'unfit cells' are eliminated from the tissue in the presence of the 'fit' ones1, 3-19.
In our recent work (Merino et al. 2022, Nature Cell Biology and Merino et al. 2022, Trends in Cell Biology) we found that Cell Competition is reminiscent of what happens in wildtype during Dpp morphogen gradient scaling. The difference between 'unfit' and 'fit' cells has been shown to be able to be encoded by different levels of Dpp signalling, and that this is reminiscent of the spatial decay of the gradient15, 16, 20-25. If the gradient is not properly scaled (i.e. if the gradient is shorter than the tissue), then a 'death program' is triggered. Indeed, this is a novel phenomenon called Death-mediated scaling3, 16, 19.
Using state-of-the-art techniques in biophysics (FRAP, FLIM, nanobody internalisation), molecular genetics and biochemistry, this project aims to unveil the mechanistic bases of the 'Death-mediated scaling' machinery during morphogen scaling and organ growth.
Lab & Institute culture
You will work in the lab, under the close supervision of the principal investigator (PI). I maintain an open door policy and aim to lead by example. The successful applicant will meet the PI at least once per week to brainstorm and discuss new research avenues.
Every member of the lab presents in the weekly lab meeting, and paper discussion activities (e.g. journal clubs) are organised to discuss the latest published research. You will have the opportunity to present your work in internal seminars run by our institution. These seminars are a valuable feedback opportunity, allowing you to profit from the exciting multidisciplinary scientific environment of the Institute of Systems, Molecular and Integrative Biology.
As part of your PhD training, you will also support at least one national conference per year, as well as one international conference within the duration of the project.
Our EDI policy
Life and research experience have taught me to create inclusive and diverse bonds in my scientific interactions. I believe this is a path to building more enriching, deep and successful research. In my career, I have promoted equity and diversity at different academic levels and I have also completed my EDI training at the University of Liverpool. As a Research Group Leader in the lab and in my teaching roles, I aim to continue to promote and expand these values (in line with those of the University). I am overall committed to the University mission of achieving research and academic excellence in an inclusive manner.
This is your place
Given the nature of this project and the excellent scientific environment available, you will use cutting-edge imaging technology and novel cell biology assays. This offers researchers the opportunity to develop original experimental skills and establish a scientific network from an early stage. Altogether, this training and support will greatly contribute to a successful PhD defence as well as to developing key and unique scientific skills.
Applications
We encourage you to apply for this position as soon as possible.
Review of applications will begin immediately and continue until the position is filled. Please note that the deadline may therefore be subject to change.
Funding Notes
Please contact the project supervisor to discuss funding possibilities.
References
Merino, M. M.; Levayer, R.; Moreno, E., Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer. Trends Cell Biol 2016, 26 (10), 776-788.
Wagstaff, L.; Kolahgar, G.; Piddini, E., Competitive cell interactions in cancer: a cellular tug of war. Trends Cell Biol 2013, 23 (4), 160-7.
M, M. M.; Gonzalez-Gaitan, M., To fit or not to fit: death decisions from morphogen fields. Trends Cell Biol 2022.
Morata, G.; Ripoll, P., Minutes: mutants of drosophila autonomously affecting cell division rate. Dev Biol 1975, 42 (2), 211-21.
Meyer, S. N.; Amoyel, M.; Bergantinos, C.; de la Cova, C.; Schertel, C.; Basler, K.; Johnston, L. A., An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 2014, 346 (6214), 1258236.
Blanco, J.; Cooper, J. C.; Baker, N. E., Roles of C/EBP class bZip proteins in the growth and cell competition of Rp ('Minute') mutants in Drosophila. Elife 2020, 9.
Vincent, J. P.; Kolahgar, G.; Gagliardi, M.; Piddini, E., Steep differences in wingless signaling trigger Myc-independent competitive cell interactions. Dev Cell 2011, 21 (2), 366-74.
Froldi, F.; Ziosi, M.; Garoia, F.; Pession, A.; Grzeschik, N. A.; Bellosta, P.; Strand, D.; Richardson, H. E.; Pession, A.; Grifoni, D., The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy. BMC Biol 2010, 8, 33.
Rodrigues, A. B.; Zoranovic, T.; Ayala-Camargo, A.; Grewal, S.; Reyes-Robles, T.; Krasny, M.; Wu, D. C.; Johnston, L. A.; Bach, E. A., Activated STAT regulates growth and induces competitive interactions independently of Myc, Yorkie, Wingless and ribosome biogenesis. Development 2012, 139 (21), 4051-61.
Chen, J.; Li, Y.; Yu, T. S.; McKay, R. M.; Burns, D. K.; Kernie, S. G.; Parada, L. F., A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012, 488 (7412), 522-6.
Tamori, Y.; Bialucha, C. U.; Tian, A. G.; Kajita, M.; Huang, Y. C.; Norman, M.; Harrison, N.; Poulton, J.; Ivanovitch, K.; Disch, L.; Liu, T.; Deng, W. M.; Fujita, Y., Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS biology 2010, 8 (7), e1000422.
Ellis, S. J.; Gomez, N. C.; Levorse, J.; Mertz, A. F.; Ge, Y.; Fuchs, E., Distinct modes of cell competition shape mammalian tissue morphogenesis. Nature 2019, 569 (7757), 497-502.
Yamamoto, M.; Ohsawa, S.; Kunimasa, K.; Igaki, T., The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 2017, 542 (7640), 246-250.
Morata, G., Cell competition: A historical perspective. Dev Biol 2021, 476, 33-40.
Merino, M. M., Azot expression in the Drosophila gut modulates organismal lifespan. Commun Integr Biol 2023, 16 (1), 2156735.
Merino, M. M.; Garcia-Sanz, J. A., Stemming Tumoral Growth: A Matter of Grotesque Organogenesis. Cells 2023, 12 (6).
Merino, M. M.; Rhiner, C.; Lopez-Gay, J. M.; Buechel, D.; Hauert, B.; Moreno, E., Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell 2015, 160 (3), 461-76.
Merino, M. M.; Rhiner, C.; Portela, M.; Moreno, E., "Fitness fingerprints" mediate physiological culling of unwanted neurons in Drosophila. Curr Biol 2013, 23 (14), 1300-9.
Merino, M. M.; Seum, C.; Dubois, M.; Gonzalez-Gaitan, M., A role for Flower and cell death in controlling morphogen gradient scaling. Nat Cell Biol 2022, 24 (4), 424-433.
Affolter, M.; Basler, K., The Decapentaplegic morphogen gradient: from pattern formation to growth regulation. Nat Rev Genet 2007, 8 (9), 663-74.
Hamaratoglu, F.; Affolter, M.; Pyrowolakis, G., Dpp/BMP signaling in flies: from molecules to biology. Semin Cell Dev Biol 2014, 32, 128-36.
Hamaratoglu, F.; de Lachapelle, A. M.; Pyrowolakis, G.; Bergmann, S.; Affolter, M., Dpp signaling activity requires Pentagone to scale with tissue size in the growing Drosophila wing imaginal disc. PLoS biology 2011, 9 (10), e1001182.
Matsuda, S.; Schaefer, J. V.; Mii, Y.; Hori, Y.; Bieli, D.; Taira, M.; Pluckthun, A.; Affolter, M., Asymmetric requirement of Dpp/BMP morphogen dispersal in the Drosophila wing disc. Nat Commun 2021, 12 (1), 6435.
Simon, N.; Safyan, A.; Pyrowolakis, G.; Matsuda, S., Dally is not essential for Dpp spreading or internalization but for Dpp stability by antagonizing Tkv-mediated Dpp internalization. 2023, 2023.01.15.524087.
Harmansa, S.; Hamaratoglu, F.; Affolter, M.; Caussinus, E., Dpp spreading is required for medial but not for lateral wing disc growth. Nature 2015, 527 (7578), 317-22.
Wagstaff, L.; Kolahgar, G.; Piddini, E., Competitive cell interactions in cancer: a cellular tug of war. Trends Cell Biol 2013, 23 (4), 160-7.
M, M. M.; Gonzalez-Gaitan, M., To fit or not to fit: death decisions from morphogen fields. Trends Cell Biol 2022.
Morata, G.; Ripoll, P., Minutes: mutants of drosophila autonomously affecting cell division rate. Dev Biol 1975, 42 (2), 211-21.
Meyer, S. N.; Amoyel, M.; Bergantinos, C.; de la Cova, C.; Schertel, C.; Basler, K.; Johnston, L. A., An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 2014, 346 (6214), 1258236.
Blanco, J.; Cooper, J. C.; Baker, N. E., Roles of C/EBP class bZip proteins in the growth and cell competition of Rp ('Minute') mutants in Drosophila. Elife 2020, 9.
Vincent, J. P.; Kolahgar, G.; Gagliardi, M.; Piddini, E., Steep differences in wingless signaling trigger Myc-independent competitive cell interactions. Dev Cell 2011, 21 (2), 366-74.
Froldi, F.; Ziosi, M.; Garoia, F.; Pession, A.; Grzeschik, N. A.; Bellosta, P.; Strand, D.; Richardson, H. E.; Pession, A.; Grifoni, D., The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy. BMC Biol 2010, 8, 33.
Rodrigues, A. B.; Zoranovic, T.; Ayala-Camargo, A.; Grewal, S.; Reyes-Robles, T.; Krasny, M.; Wu, D. C.; Johnston, L. A.; Bach, E. A., Activated STAT regulates growth and induces competitive interactions independently of Myc, Yorkie, Wingless and ribosome biogenesis. Development 2012, 139 (21), 4051-61.
Chen, J.; Li, Y.; Yu, T. S.; McKay, R. M.; Burns, D. K.; Kernie, S. G.; Parada, L. F., A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012, 488 (7412), 522-6.
Tamori, Y.; Bialucha, C. U.; Tian, A. G.; Kajita, M.; Huang, Y. C.; Norman, M.; Harrison, N.; Poulton, J.; Ivanovitch, K.; Disch, L.; Liu, T.; Deng, W. M.; Fujita, Y., Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS biology 2010, 8 (7), e1000422.
Ellis, S. J.; Gomez, N. C.; Levorse, J.; Mertz, A. F.; Ge, Y.; Fuchs, E., Distinct modes of cell competition shape mammalian tissue morphogenesis. Nature 2019, 569 (7757), 497-502.
Yamamoto, M.; Ohsawa, S.; Kunimasa, K.; Igaki, T., The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 2017, 542 (7640), 246-250.
Morata, G., Cell competition: A historical perspective. Dev Biol 2021, 476, 33-40.
Merino, M. M., Azot expression in the Drosophila gut modulates organismal lifespan. Commun Integr Biol 2023, 16 (1), 2156735.
Merino, M. M.; Garcia-Sanz, J. A., Stemming Tumoral Growth: A Matter of Grotesque Organogenesis. Cells 2023, 12 (6).
Merino, M. M.; Rhiner, C.; Lopez-Gay, J. M.; Buechel, D.; Hauert, B.; Moreno, E., Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell 2015, 160 (3), 461-76.
Merino, M. M.; Rhiner, C.; Portela, M.; Moreno, E., "Fitness fingerprints" mediate physiological culling of unwanted neurons in Drosophila. Curr Biol 2013, 23 (14), 1300-9.
Merino, M. M.; Seum, C.; Dubois, M.; Gonzalez-Gaitan, M., A role for Flower and cell death in controlling morphogen gradient scaling. Nat Cell Biol 2022, 24 (4), 424-433.
Affolter, M.; Basler, K., The Decapentaplegic morphogen gradient: from pattern formation to growth regulation. Nat Rev Genet 2007, 8 (9), 663-74.
Hamaratoglu, F.; Affolter, M.; Pyrowolakis, G., Dpp/BMP signaling in flies: from molecules to biology. Semin Cell Dev Biol 2014, 32, 128-36.
Hamaratoglu, F.; de Lachapelle, A. M.; Pyrowolakis, G.; Bergmann, S.; Affolter, M., Dpp signaling activity requires Pentagone to scale with tissue size in the growing Drosophila wing imaginal disc. PLoS biology 2011, 9 (10), e1001182.
Matsuda, S.; Schaefer, J. V.; Mii, Y.; Hori, Y.; Bieli, D.; Taira, M.; Pluckthun, A.; Affolter, M., Asymmetric requirement of Dpp/BMP morphogen dispersal in the Drosophila wing disc. Nat Commun 2021, 12 (1), 6435.
Simon, N.; Safyan, A.; Pyrowolakis, G.; Matsuda, S., Dally is not essential for Dpp spreading or internalization but for Dpp stability by antagonizing Tkv-mediated Dpp internalization. 2023, 2023.01.15.524087.
Harmansa, S.; Hamaratoglu, F.; Affolter, M.; Caussinus, E., Dpp spreading is required for medial but not for lateral wing disc growth. Nature 2015, 527 (7578), 317-22.
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