Role of Notch signalling during neural crest migration

Lead Research Organisation: King's College London
Department Name: Randall Div of Cell and Molecular Biophy

Abstract

The ability of cells to migrate is fundamental for many biological processes, from embryo formation to cancer progression. During embryo development thousands of different cell types are generated, these have to migrate from their original positions to be functional. For example pigment cells are born on top of the embryonic spinal cord, from where they migrate and colonise the skin of the entire body. In cancer, migration of metastatic cells away from the original tumour is responsible for the formation of secondary tumours. This process has catastrophic consequences, being responsible for 90% of deaths of cancer patients. Understanding the mechanisms controlling cell migration is therefore a major question for biology and medicine.
Cell migration has three main steps. First, cells have to detach from their neighbours to become free to move. Second, they have to decide where to go and finally, they have to recognise when their journey is over. The objective of my project is to understand which set of molecules control these steps.
To study these questions we will use neural crest cells as a model system. Neural crest cells are born early during embryogenesis, they migrate extensively and differentiate in many cell types (neurons, pigments cells, cartilage, etc). Because of their early formation during embryogenesis, neural crest are easily accessible for direct experimentation. Moreover, their migratory behaviour shares many features with that of other migratory cells, including cancer cells, making neural crest cells an ideal system to study cell movement.
In this project, I will study neural crest migration in fish embryos. Fish are easy to rise in the laboratory and produce large numbers of embryos. These embryos are transparent, enabling us to film neural crest cells and watch, in real time, how they connect to their neighbours, how their shape changes and how they move. Importantly in fish, we can modify the genes we think control migration and then test the effects of these changes in cell movement: are cells detaching normally? Is cell shape changed? And how do they move? The answers to these questions will allow us to decide which genes are important for cell migration.
In conclusion, this study will provide us with a better understanding of cell migration and we will learn, which genes control this process. Importantly, it can also help us to identify new target molecules for cancer therapies.

Technical Summary

Cell migration is essential for many biological processes such as embryogenesis, wound healing, and tissue homeostasis. In cancer, cell migration plays a critical role during tumour metastasis and is responsible for 90% of deaths of these patients. Despite its importance, it remains one of the most poorly understood aspects of cancer pathogenesis.
Because neural crest cells undergo extensive migration in the embryo and share numerous characteristics with metastatic cells, they represent an important model system for studying cell migration. Although neural crest and cancer cell migration have historically been considered from the perspective of single cells moving independently, metastatic cells are frequently found migrating in groups, a process known as collective cell migration. Importantly, collective cell migration endows cancer cells with a higher capacity to disseminate and increased efficiency of metastasis.
The aim of this project is to investigate aspects of collective neural crest migration in zebrafish embryos, focusing on the role that the Notch pathway plays in this process. My preliminary data suggest an important role for Notch signalling in neural crest migration. The proposed experiments will expand upon these preliminary results by combining the power of genetics, offered by zebrafish transgenic lines, with live cell imaging and the generation of new tools to study single genetically altered cells in vivo.
These approaches will provide a detailed molecular and cellular analysis of neural crest migration. Given the importance of cell migration in tissue homeostasis and its implication in many types of cancers, our findings in neural crest cells will shed light on the mechanism of metastasis and may unveil novel targets for cancer therapies.
 
Description Parenting Leave Fund
Amount £20,000 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 08/2013 
End 12/2013
 
Description The genetic control of collective cell migration: insights from the neural crest
Amount £99,939 (GBP)
Funding ID 207630/Z/17/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2017 
End 08/2019
 
Description Bioinformatic networc analysis of Neural Crest transcriptomics (Sanz Moreno) 
Organisation King's College London
Department Randall Division of Cell & Molecular Biophysics
Country United Kingdom 
Sector Academic/University 
PI Contribution Our group has recovered transcriptomic data sets from different Neural Crest animal models and will be generating RNA-seq for zebrafish Neural Crest of defined identities.
Collaborator Contribution The group of Dr Sanz Moreno has develop a plethora of OMICs (transcriptomics, proteomics and metabolomics) tools to analyze cancer cell migration. Her team will participate to the bioinformatics and genetic network analysis of the RNA-seq data sets.
Impact We are submitting a Wellcome Seed Award in collaboration
Start Year 2016
 
Description Computational modelling of Neural Crest Collective migration 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution My laboratory has quantitatively studied the behavior of collectively migrating trunk Neural Crest, the role of Notch lateral inhibition and cell cycle progression in this process, through the use of live imaging and genetic perturbations.
Collaborator Contribution The group of Katie Bentley has develop computational models that allow the integration of the different pathways we are studying, allows in silico experimentation and generation of new predictions and hypothesis.
Impact We have sent a BBSRC grant in collaboration
Start Year 2018
 
Description Genetic network regulating neural crest guidance 
Organisation The Wellcome Trust Sanger Institute
Department Vertebrate Genetics and Genomics
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Our team has develop new computational quantitative tools and zebrafish lines for the analysis of Neural Crest migration
Collaborator Contribution Dr Busch-Nentwich has generated trasncriptomic data and mutant and transgenic lines that we are using in collaboration to analyze the collective guidance mechanisms of neural crest cells.
Impact We have submitted a BBSRC project grant
Start Year 2015
 
Description Mathematical analysis of Neural Crest migration 
Organisation University of Cambridge
Department Institute of Astronomy
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated in vivo quantitative data describing Neural Crest migration in wild type and transgenic embryos
Collaborator Contribution The Kabla group has generated the required tools to analyze the characteristics of Neural Crest migration, allowing us to test our current hypothesis as well as to propose new models.
Impact Paper publication Richardson et al. 2016 Cell Reports
Start Year 2015
 
Description Role of Notch signalling during neural crest migration (Hartel) 
Organisation University of Chile
Country Chile 
Sector Academic/University 
PI Contribution Our lab is investigation the control of Neural Crest cell migration by the Notch signalling pathway. We are analysing cell movement by in vivo imaging.
Collaborator Contribution The SCIAN laboratory is mathematically analysing our movies. Specific computer programs are being generated for this purpose.
Impact The project only started this year and no outcome has been produced yet. This is a multi-disiplinary collaboration. Our laboratory is focus in the production of the biological data. Our collaborator expertise is mathematical analysis of these data.
Start Year 2011
 
Description Role of cell cycle progression in neural crest migration (Prince) 
Organisation University of Chicago
Country United States 
Sector Academic/University 
PI Contribution My group is how the progression through the cell cycle influence neural crest migration.
Collaborator Contribution The group of Victoria Prince at the Department of Organismal Biology & Anatomy, University of Chicago, is performing a complementary analysis using different methodology.
Impact We have submitted an International Exchange Award to the Royal Society.
Start Year 2017
 
Description Study of cranial neural crest collective migration (Mayor) 
Organisation University College London
Department Department of Cell and Developmental Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Our team has generated several zebrafish transgenic lines to study neural crest formation, migration and differentiation with time and spacial resolution.
Collaborator Contribution Prof Mayor is analyzing the process of cranial neural crest migration.
Impact We have coauthored the following paper: Moore R, Theveneau E, Pozzi S, Alexandre P, Richardson J, Merks A, Parsons M, Kashef J, Linker C, Mayor R.(2013) Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion. Development. 140(23):4763-75. Contributed to the experimental design, performance of experiments and writing the paper. DOI: 10.1242/dev.098509
Start Year 2012
 
Description Tissue interaction regulating trunk neural crest migration 
Organisation Eberhard Karls University of Tubingen
Country Germany 
Sector Academic/University 
PI Contribution Our team has develop new computational quantitative tools and zebrafish lines for the analysis of Neural Crest migration
Collaborator Contribution In collaboration with the team of Prof Nuesslein-Volhard we have developed preliminary data and propose a new model for Trunk Neural Crest guidance
Impact This collaboration has produced the following publication Singh, AP, Dinwiddie, A, Mahalwar, P, Schach, U, Linker, C, Irion, U, Nüsslein-Volhard, C. (2016) Multipotent and plastic progenitors for adult pigment cells in zebrafish. Dev Cell. Aug 8;38(3):316-30. Contributed to experimental results and the writing of the paper. DOI:10.1016/j.devcel.2016.06.020
Start Year 2016
 
Description Transcriptional regulation of neural crest collective migration (Sauka-Spengler) 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Academic/University 
PI Contribution Our team has defined the cellular interactions and traits of neural crest collective migration.
Collaborator Contribution Dr Sauka-Spengler has defined and characterised the gene regulatory network underlying neural crest formation in vertebrates. Her laboratory is at the forefront of neural crest genomics and in collaboration we will generate RNA-seq data sets for define neural crest populations.
Impact We are submitting a Wellcome Seed Award
Start Year 2016
 
Description In2Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact School students from disadvantaged backgrounds shadow a member of the laboratory for a week.
Year(s) Of Engagement Activity 2019
URL https://in2scienceuk.org/
 
Description King's College Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Two groups of 30 people attended my talk, this was followed by questions and discussion.

I don't have this information.
Year(s) Of Engagement Activity 2011
 
Description Shadow a Scientist 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact Medical students participate to research activities in the laboratory
Year(s) Of Engagement Activity 2017,2018,2019
 
Description The National Student Association of Medical Research (NSAMR) tester month 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Undergraduate medical students shadowed the lab work for a few days
Year(s) Of Engagement Activity 2016
URL http://www.nsamr.org/research/taster-month/