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Cellular mechanisms of organ self-assembly in vivo

English title Cellular mechanisms of organ self-assembly in vivo
Applicant Gilmour Darren
Number 176235
Funding scheme Project funding (Div. I-III)
Research institution Institut für Molekulare Biologie (IMLS) Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Cellular Biology, Cytology
Start/End 01.01.2018 - 30.04.2021
Approved amount 678'000.00
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All Disciplines (3)

Discipline
Cellular Biology, Cytology
Embryology, Developmental Biology
Genetics

Keywords (4)

Morphogenesis ; Signalling; Optogenetics; Cell polarity

Lay Summary (Italian)

Lead
In sintesiQuesta proposta intende stabilire quali sono le transizioni molecolari e cellulari che portano cellule mesenchimali pluripotenti ad auto-assemblarsi per formare organi sensoriali. L’obiettivo e’ capire l'incredibile “robustness” che caratterizza il programma di sviluppo embrionale e fornire nuovi ed importanti contributi al campo emergente della biologia degli organoidi.
Lay summary

Soggetto e obiettivi

Decenni di ricerca hanno stabilito che lo sviluppo embrionale è un processo “a cascata” in cui i tessuti vengono progressivamente suddivisi da una serie di geni “patterning” ed ogni passo in avanti costituisce un modello per quello successivo. Lavori recenti hanno tuttavia dimostrato che le cellule staminali in vitro possono organizzarsi e formare organoidi, come i "mini cervelli" e le orecchie interne, in assenza di schemi preesistenti o di vincoli fisici. Ovviamente, un tale "auto-assemblaggio" non è un'invenzione degli organoidi, piuttosto questi studi rivelano l’alto grado di plasticità che caratterizza la formazione di organi, un aspetto questo poco conosciuto a causa della mancanza di modelli idonei. Per tanto studi in vivo su come gli organi si formano al di fuori del loro normale programma potrebbero spiegare l'incredibile resistenza che caratterizza lo sviluppo embrionale e contribuire al campo emergente della biologia degli organoidi.

Lo scopo di questa proposta è di studiare i cambiamenti molecolari e cellulari che caratterizzano l’auto-assemblaggio degli organi sensoriali negli embrioni di zebrafish. Cominceremo confrontando gli organi sensoriali epiteliali con i loro progenitori mesenchimali pluripotenti per determinare le differenze genetiche, cellulari e meccaniche. Utilizzeremo strumenti “optogenetici” per attivare con grande precisione spaziotemporale l’assemblaggio degli organi sensoriali in embrioni viventi. Questi esperimenti mirati risponderanno ad importanti domande, per esempio, come viene iniziata e propagata in cellule pluripotenti l’ organizzazione epiteliale per capire quali sono i meccanismi che controllano l’assemblaggio di questi organi. Le conoscenze derivanti dallo studio del nostro modello animale in vivo saranno estese allo sviluppo di organoidi umani dell’orecchio interno.

Direct link to Lay Summary Last update: 02.11.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
An image-based data-driven analysis of cellular architecture in a developing tissue
Hartmann Jonas, Wong Mie, Gallo Elisa, Gilmour Darren (2020), An image-based data-driven analysis of cellular architecture in a developing tissue, in eLife, 9, NA-NA.
Dynamic Buffering of Extracellular Chemokine by a Dedicated Scavenger Pathway Enables Robust Adaptation during Directed Tissue Migration
Wong Mie, Newton Lionel R, Hartmann Jonas, Hennrich Marco L, Wachsmuth Malte, Ronchi Paolo, Guzmán-Herrera Alejandra, Schwab Yannick, Gavin Anne-Claude, Gilmour Darren (2020), Dynamic Buffering of Extracellular Chemokine by a Dedicated Scavenger Pathway Enables Robust Adaptation during Directed Tissue Migration, in Developmental cell, 52(4), 492-508.
Getting back on track: exploiting canalization to uncover the mechanisms of developmental robustness
Wong Mie, Gilmour Darren (2020), Getting back on track: exploiting canalization to uncover the mechanisms of developmental robustness, in Current opinion in genetics & development, 63, 53-60.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss Zebrafish Conference Talk given at a conference A morphometric framework for the embryo-wide quantification of tissue organisation at single cell resolution 08.04.2021 Zurich (online), Switzerland Brambach Max;
Swiss Zebrafish Conference Talk given at a conference Triggering Organ Self-Assembly in vivo Via Targeted Manipulation of Cellular Architecture 08.04.2021 Zurich (online), Switzerland Ebnicher Greta;
Swiss Zebrafish Conference Poster Addressing the interplay of cell motility, tissue organization and tissue differentiation in the embryonic zebrafish epidermis 08.04.2021 Zurich (online), Switzerland Bill Robert;
Swiss Cytomeet Conference Talk given at a conference Keynote Lecture: Mechanisms ensuring robust tissue migration through changing guidance landscapes 19.01.2021 Bern (online), Switzerland Gilmour Darren;
European Developmental Biology Conference Talk given at a conference A NOVEL ADAPTATION MECHANISM TO ENSURE ROBUST TISSUE MIGRATION VIA DYNAMIC BUFFERING OF EXTRACELLULAR CHEMOKINE 23.10.2019 Alicante , Spain Wong Mie;
Royal Society Meeting on Contemporary Morphogenesis Talk given at a conference Cellular Mechanisms of Organ Self-Assembly In Vivo 07.10.2019 London, Great Britain and Northern Ireland Gilmour Darren;
EMBO EMBL Symposium: Synthetic Morphogenesis Talk given at a conference Mechanisms underlying robust tissue behavior in changing environments 17.03.2019 Heidelberg, Germany Gilmour Darren;
Gordon Research Conference Cell Migration Talk given at a conference Cellular Mechanisms Ensuring Robust Tissue Migration Through Changing Environments 20.01.2019 Galveston, Texas, United States of America Gilmour Darren;
MIC Symposium on Multiscale Imaging Talk given at a conference Organ Assembly: From Single Cell To Cell Collective and Back 30.11.2018 Bern, Switzerland Gilmour Darren;
EMBO|EMBL Symposium: Tissue Self-Organisation Talk given at a conference From Single Cell To Cell Collective And Back 12.03.2018 Heidelberg, Germany Gilmour Darren;


Awards

Title Year
Forschungskredit Candoc Prize 2021
SNSF Scientific Image Competition, Jury Distinction 2020
Speaker Prize, European Developmental Biology Conference 2019

Associated projects

Number Title Start Funding scheme
189781 A photo-manipulation unit for high precision, 3-dimensional photoactivation and laser ablation on a multi-view light sheet microscope setup 01.12.2019 R'EQUIP

Abstract

Decades of research have established that embryonic development is a hierarchical process where tissues become progressively subdivided by a cascade of ‘patterning’ genes, with each step forming a template for the next. However, recent work has shown that pluripotent cells in vitro can assemble into organoids, such as ‘mini brains’ and inner ears, in the absence external pre-patterns or physical constraints. Obviously, such ‘self-assembly’ is not an invention of organoids, rather these in vitro studies have uncovered aspects of organogenesis that are poorly understood in vivo, due to a lack of suitable models. Thus, in vivo studies that specifically address how organs assemble outside of their normal program could help explain the incredible robustness of development and provide important contributions to the emerging field of organoid biology.The zebrafish lateral line is a series of sensory ‘mini ear’ organs that detect pressure changes in the surrounding water. The organs of the larval fish are deposited as epithelial rosette assemblies by a migrating primordium, and we have studied this process to uncover mechanisms of collective migration. By contrast, the adult organs arise from mesenchymal interneuromast ‘chain’ cells that are also deposited by the migrating primordium. This late organogenesis occurs in specific subsets of chain cells in a precise temporal order. However, unpublished work from our lab indicates that organogenesis can be triggered on demand by activating FGF signalling in any cell of this precursor population. The simple organisation of these precursor cells, combined with the ability to activate organogenesis on demand, makes this an exciting new model to investigate autonomous assembly in vivo.The aim of this proposal is to investigate cell state transition mechanisms underlying organ self-assembly in living zebrafish embryos. We will begin by carefully defining and comparing two cell types - epithelial sensory organs and their pluripotent mesenchymal progenitors - in terms of genetic, cellular and mechanical differences. We will use optogenetic tools to activate the organ assembly program with unprecedented spatiotemporal precision in living embryos. Targeted experiments will be applied to answer several key questions, such how epithelial polarity is initiated and propagated across pluripotent cell populations, and to investigate the mechanism underlying robust organ assembly. Mechanistic insights gained from our in vivo animal model will be applied to the development of human inner ear organoids.
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