Epithelial morphogenesis and cell polarity
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
"Epithelial cell polarity specification and maintenance is a key problem in cell biology. The vast majority of cancers in human originate from epithelia (i.e. Breast, Colon, Lung, Kidney, etc.) and a major hallmark of tumourogenesis is a progressive loss of epithelial cell polarity. We are studying this problem using the fruit fly Drosophila melanogaster, coming with an unparalleled genetic toolbox, and thus allowing us to manipulate the function of virtually every single gene present in its genome. While up to 80% of the genes associated with diseases in human are conserved in Drosophila, they are often present as one single gene, which is ideal to study a gene function, as very little redundancy is present. Using this approach, we are making significant progresses toward characterizing the molecular basis for establishing and maintaining epithelial cell polarity. This is particularly relevant for better tackling the process of tumorogenesis and metastasis, as these are characterized by a loss of epithelial cell polarity."
Technical Summary
"The regulation of Epithelial cell polarity specification and maintenance is a key problem in cell biology. The vast majority of cancers in human originate from epithelia (i.e. Breast, Colon, Lung, Kidney etc.) and a major hallmark of tumourogenesis is a progressive loss of epithelial cell polarity. This eventually leads to Epithelial to Mesenchymal (EMT) cell transition a key step toward cell metastasis activity. Epithelial cell specification presents the converse step (i.e. Mesenchymal to Epithelial transition, MET). Better understanding the molecular mechanisms and signalling pathways required for promoting MET is therefore a key step toward a better understanding of EMT.||To tackle this question in vivo, we are using the genetically amenable Drosophila melanogaster. While up to 80% of the genes associated with diseases in human, are conserved in Drosophila, they are often present as one single locus, which is ideal as very little redundancy is present. So far this approach has allowed us to characterize the function of the conserved tumour suppressor PTEN, during epithelial apical membrane morphogenesis. PTEN is mutated in more than 50% of cancers in human. In epithelial cells, PTEN is recruited at the developing zonula adherens (za) through direct binding to the conserved polarity gene Par3/Baz. Our work in Drosophila has now been confirmed and validated in mammalian epithelial cells, by two other independent groups. Since then, we have tried to better characterize the PTEN/Par3 interface and in particular we have focussed our work on the problem of za morphogenesis and maintenance. The za is the principal membrane domain for the cells to form an epithelial sheet, as this domain is responsible for cell-cell anchorage. We believe that we have now solved a number of key open questions in this field of research. In particular, we have recently solved the molecular basis for Par3 requirement during za assembly in epithelial cells. Par3 and PTEN are also key genes for directed cell migration and we propose that in pathological conditions such as cancer, defect in their regulation in epithelial cells (i.e. phosphorylations/localization), and are likely to have a profound impact toward cell metastasis."
Publications
Mencarelli C
(2018)
RanBP1 Couples Nuclear Export and Golgi Regulation through LKB1 to Promote Cortical Neuron Polarity.
in Cell reports
Walther RF
(2016)
Pak4 Is Required during Epithelial Polarity Remodeling through Regulating AJ Stability and Bazooka Retention at the ZA.
in Cell reports
Blackie L
(2021)
A combination of Notch signaling, preferential adhesion and endocytosis induces a slow mode of cell intercalation in the Drosophila retina.
in Development (Cambridge, England)
Nunes De Almeida F
(2019)
Cdc42 defines apical identity and regulates epithelial morphogenesis by promoting apical recruitment of Par6-aPKC and Crumbs.
in Development (Cambridge, England)
Barriga EH
(2022)
RanBP1 plays an essential role in directed migration of neural crest cells during development.
in Developmental biology
Pichaud F
(2014)
Transcriptional regulation of tissue organization and cell morphogenesis: the fly retina as a case study.
in Developmental biology
Rosa A
(2015)
Ect2/Pbl acts via Rho and polarity proteins to direct the assembly of an isotropic actomyosin cortex upon mitotic entry.
in Developmental cell
Pichaud F
(2018)
PAR-Complex and Crumbs Function During Photoreceptor Morphogenesis and Retinal Degeneration.
in Frontiers in cellular neuroscience
Walther RF
(2018)
Rap1, Canoe and Mbt cooperate with Bazooka to promote zonula adherens assembly in the fly photoreceptor.
in Journal of cell science
Chung GHC
(2022)
The ultrastructural organization of endoplasmic reticulum-plasma membrane contacts is conserved in epithelial cells.
in Molecular biology of the cell
Blackie L
(2020)
Cell-type-specific mechanical response and myosin dynamics during retinal lens development in Drosophila.
in Molecular biology of the cell
Zihni C
(2017)
An apical MRCK-driven morphogenetic pathway controls epithelial polarity.
in Nature cell biology
Mencarelli C
(2015)
Orthodenticle Is Required for the Expression of Principal Recognition Molecules That Control Axon Targeting in the Drosophila Retina.
in PLoS genetics
Pichaud F
(2022)
Shaping an optical dome: The size and shape of the insect compound eye.
in Seminars in cell & developmental biology
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_12018/1 | 31/07/2013 | 30/03/2017 | £1,079,000 | ||
MC_UU_12018/2 | Transfer | MC_UU_12018/1 | 31/07/2013 | 30/03/2017 | £989,000 |
MC_UU_12018/3 | Transfer | MC_UU_12018/2 | 31/07/2013 | 30/03/2017 | £925,000 |
MC_UU_12018/4 | Transfer | MC_UU_12018/3 | 31/07/2013 | 30/03/2017 | £908,000 |
MC_UU_12018/5 | Transfer | MC_UU_12018/4 | 31/07/2013 | 30/03/2017 | £1,560,000 |
MC_UU_12018/6 | Transfer | MC_UU_12018/5 | 31/07/2013 | 30/03/2017 | £1,234,000 |
MC_UU_12018/7 | Transfer | MC_UU_12018/6 | 31/07/2013 | 30/03/2017 | £1,070,000 |
Description | BBSRC Alert16 - Lattice sheet microscope |
Amount | £569,000 (GBP) |
Funding ID | BB/R000697/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2017 |
End | 08/2018 |
Description | Multi-user equipment grant |
Amount | £290,000 (GBP) |
Funding ID | 108427/z/15/z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2014 |
End | 09/2019 |
Title | Optimising Lattice sheet microscopy |
Description | developing new approaches to low photo-toxicity microscopy. |
Type Of Material | Technology assay or reagent |
Year Produced | 2018 |
Provided To Others? | No |
Impact | Panned grant applications. |
Description | Ect2- Cdc42 and Mitotic rounding |
Organisation | University College London |
Department | MRC Laboratory for Molecular Cell Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided biochemical evidence that the GEF Ect2 binds to Par6 and Cdc42 in Drosophila |
Collaborator Contribution | The Baum lab has identified a major role for Ect-2 during mitotic cell rounding and remodelling of epithelial polarity in this particular context. |
Impact | Ect2/Pbl Acts via Rho and Polarity Proteins to Direct the Assembly of an Isotropic Actomyosin Cortex upon Mitotic Entry André Rosa, Evi Vlassaks, Franck Pichaud, Buzz Baum Dev Cell. 2015 March 9; 32(5): 604-616. doi: 10.1016/j.devcel.2015.01.012 PMCID: PMC4359025 |
Start Year | 2014 |
Description | Mechanical forces involved in neuroepithelial morphogenesis |
Organisation | University College London |
Department | MRC Laboratory for Molecular Cell Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Live imaging of developing retina - systematic study of the forces at play during neuro-epithelial morphogenesis including asymmetric cell division. |
Collaborator Contribution | The Mao (LMCB) lab is helping us with in silica models of ommatidial cell patterning during retinal development. The Banerjee (UCL, IPLS/FLS) lab is helping us with PIV analysis of Myosin activity in ommatidial cells during ommatidial patterning |
Impact | paper |
Start Year | 2014 |
Description | Mechanisms of actomyosin force regulation during epithelial tissue patterning |
Organisation | University College London |
Department | Institute for the Physics of Living Systems |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Using the developing fly retina as a model system to study sensory epithelium patterning. |
Collaborator Contribution | Shila Barnerjee (UCL- IPLS) and Yanlan Mao (UCL-MRC LMCB/IPLS) are providing us with expertise on how to analyse Myosin2 during multicellular patterning. |
Impact | Research paper in preparation. Joint grant submission to follow up on our work (BBSRC) |
Start Year | 2017 |
Description | Regulation of Cdc42 in epithelial cells |
Organisation | University College London |
Department | Institute of Ophthalmology UCL |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Discovery that RhoGap19D regulates Cdc42 during epithelial apical membrane differentiation |
Collaborator Contribution | Matter lab: Expanding our finding to mammalian cell cultures (Caco cells) |
Impact | Paper published on 2017 : An apical MRCK-driven morphogenetic pathway controls epithelial polarity. Zihni C, Vlassaks E, Terry S, Carlton J, Leung TKC, Olson M, Pichaud F, Balda MS, Matter K. Nat Cell Biol. 2017 Sep;19(9):1049-1060. doi: 10.1038/ncb3592. Epub 2017 Aug 21. |
Start Year | 2014 |
Description | Role of Pak4 during epithelial membrane differentiation |
Organisation | Memorial Sloan Kettering Cancer Center |
Department | Cell Biology Program |
Country | United States |
Sector | Academic/University |
PI Contribution | Discovery that Drosophila pak4 is regulates the epithelial polarity gene network. |
Collaborator Contribution | Identification of the epithelial protein Par6 as a substrate for Pak4 |
Impact | This collaboration has consisted in capitalising on Drosophila genetics to determine exactly where Pak4 fits in the existing network of epithelial polarity genes. In my lab, this has meant establishing and studying the relevant Par6 and Pak4 transgenic animals. Corresponding paper submitted Oct 2015 |
Start Year | 2014 |
Description | Role of RhoGAP19D and Ect2 during epithelial polarity remodelling |
Organisation | University College London |
Department | Institute of Ophthalmology UCL |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Characterisation of the role of RhoGAP19D and Ect2 during epithelial polarity remodelling in vivo. This includes generating novel mutants for RhoGAP19D has none existed prior to our work |
Collaborator Contribution | The lab of Karl Matter is providing us with expertise on vertebrate cell culture. This lab is examining the function of the RhoGAP19D ortholog that we have identified in MDCK cells. In Parallel, we realised that part of our work on Ect2 was highly relevant for another project at the MRC-LMCB. This initiated a collaboration with the lab of Buzz Baum which led to a publication in 2015. |
Impact | We have generated a mutant in the RhoGAP19D locus that we are using to characterise the function of this particular Cdc42 GEF during epithelial cell polarity remodelling. This collaboration allows us to examine this function in Drosophila (in vivo) and vertebrates (in vitro). Ect2/Pbl Acts via Rho and Polarity Proteins to Direct the Assembly of an Isotropic Actomyosin Cortex upon Mitotic Entry André Rosa, Evi Vlassaks, Franck Pichaud, Buzz Baum Dev Cell. 2015 March 9; 32(5): 604-616. doi: 10.1016/j.devcel.2015.01.012 PMCID: PMC4359025 |
Start Year | 2013 |
Description | Super Resolution imaging |
Organisation | National Physical Laboratory |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Working together with NPL toward establishing a regional user platform for super resolution imaging. |
Collaborator Contribution | NPL assembles experimental super resolution system. |
Impact | The setting up of a core facility for super resolution at UCL is now well underway. |
Start Year | 2011 |
Description | MRC blog featuring research in my lab |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | wrote a blog in collaboration with the MRC. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.insight.mrc.ac.uk/ |
Description | Tweeter feed - Cell polarity@pichaud lab |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Tweeter feed to promote our work on epithelial cell polarity. |
Year(s) Of Engagement Activity | 2016 |
URL | https://twitter.com/PichaudLab |