Membrane dynamics and developmental signalling in Zebrafish and Drosophila

Biological membranes act both as boundaries between different cellular compartments and as interfaces for cell-cell communication. We use the zebrafish Danio rerio and the fruitfly Drosophila melanogaster to study the importance of the shape of cellular membranes for the control of cell signalling in animal development: Invaginations of the plasma membrane allow forming endocytic vesicles that remove signalling molecules from the cell surface. Conversely, protrusions of the plasmalemma into the extracellular space allow a cell to probe its environment (Fig.1). Our work at the interface between cellular and developmental biology aims to address three parameters that are critical to regulate the activity of membrane-bound signalling molecules 1) the localization of a signalling molecule in the cell; 2) the shape of the membrane itself; and 3) the dynamic remodelling of cellular membranes in the course of animal development


Fig 1 : Topologically opposite membrane bending involved
in endoyctosis and ciliogenesis.

 

1- Localizing Delta ligands in the zebrafish neuroepithelium.

Membranes are not homogeneous lipid bilayers, but organized into different functional domains. Consequently, signalling molecules have to be targeted to precise environments to exert their function. This is particularly apparent in the case of polarized epithelial cells, which present distinct apical and baso-lateral membrane domains that are separated by junctional complexes. We are interested in understanding how intracellular endocytic transport affects the localisation and activity of Delta ligands and their Notch receptors. From flies to men, Delta/Notch signalling is of major importance for embryonic development as well as for the maintenance of adult stem cells. While it is presently clear that endocytic internalization of Delta ligands is essential for Notch activation, the actual reason for this requirement remains mysterious. We have established a novel live imaging assay that allows for the first time to visualize the intracellular transport of endogenous DeltaA ligands in the neuroepithelium of living intact zebrafish embryos (Movie 1). Using this approach, we will dissect the mechanisms that govern ligand transport and determine their importance for Notch signalling in vertebrate neural development.

 

 


Movie1 : Endocytic transport of Delta ligand molecules
in the zebrafish neural tube
.
2 - Shaping a signalling antenna: analysis of a novel pathway in ciliogenesis

Fig 2 : Malformations of the inner ear (A) and loss of mecanosensory
lateral line cilia (B) in Morpholino knock-down animals
.

Cilia are highly specialized membrane domains that comprise a protrusion of the plasma membrane surrounding a central microtubule scaffold (the ciliary axoneme). After being long time neglected, recent years have shown that these organelles are of major importance for both embryonic development and adult health. Different types of cilia enable cells to communicate with their environment: Sensory cilia perceive mechanical stimuli or odors. Motile cilia drive extracellular fluid flows that are important for processes such as the establishment of left/right asymmetry or the morphogenesis of the inner ear. Finally, small primary cilia are essential for Hedgehog-mediated growth factor signalling. We use the zebrafish as model system to study the developmental function of proteins that are known to be implicated in cellular membrane remodelling. Unexpectedly, this has led us to uncover a novel function of these proteins in ciliogenesis (Fig.2). Presently we are using a combination of genetic, cell biological and biophysical approaches in zebrafish and Drosophila to characterize this novel aspect of ciliary biogenesis.

 

 

3 - Dynamic remodelling of signalling endosomes during cell division.

One of the most dramatic membrane remodelling events is cell division. Recent studies show that intracellular endocytic trafficking is required to re-shape the plasma membrane during mitosis. By studying Drosophila sensory bristle development we have obtained evidence that a special type of signalling endosome is asymmetrically segregated during asymmetric cell division to promote Notch signalling in one of the two daugther cells (Movie 2). Interestingly, the membranes of these endosomes are themselves extensively remodelled during mitosis, concurrent with the activation of Notch signalling. Taken together, these observations raise the question whether cell-cycle dependent endosomal membrane remodelling may regulate the activity of internalized signalling molecules and act as a temporal trigger for receptor activation. We will use Drosophila sensory bristles and the zebrafish retina, two systems were signalling is coordinated with cell division, to study the importance of cell-cycle dependent endosomal membrane remodelling for the coordination of cell division and cell signalling during animal development.


Movie 2 : Asymmetric segregation of Delta-containing endosomes during asymmetric cell division.

 

Last publications

Biogenesis and function of ESCRT-dependent extracellular vesicles. - 2017 - Seminars in cell & developmental biology - Juan T, and Fürthauer,M

The ESCRT machinery: When function follows form. - 2017 - Seminars in cell & developmental biology - Fürthauer,M

ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors. - 2016 - Science signaling - 9 Pra8 - MamiÅ„ska A, Bartosik A, Banach-OrÅ‚owska M, Pilecka I, JastrzÄ™bski K, Zdżalik-Bielecka D, Castanon I, Poulain M, Neyen C, WoliÅ„ska-NizioÅ‚ L, ToruÅ„ A, SzymaÅ„ska E, Kowalczyk A, Piwocka K, Simonsen A, Stenmark H, Fì¼rthauer M, González-Gaitán M, and Miaczynska,M

Directional Notch trafficking in Sara endosomes during asymmetric cell division in the spinal cord. - 2015 - Nature cell biology - 17 P333-9 - Kressmann S, Campos C, Castanon I, Fì¼rthauer M, and González-Gaitán,M

[The ESCRT complex: from endosomal transport to the development of multicellular organisms]. - 2015 - Biologie aujourd'hui - 209 P111-24 - Juan T, and Fürthauer,M

Systems dynamics in endocytosis. - 2014 - Traffic - 15 P338-46 - Fürthauer M, and Smythe,E

Uninflatable and Notch Control the Targeting of Sara Endosomes during Asymmetric Division. - 2014 - Current biology : CB - Loubéry S, Seum C, Moraleda A, Daeden A, Fì¼rthauer M, and Gonzalez-Gaitan,M

The ESCRT machinery regulates the secretion and long-range activity of Hedgehog. - 2014 - Nature - 516 P99-103 - Matusek T, Wendler F, Polès S, Pizette S, D'Angelo G, Fürthauer M, and Thérond,PP

Report of the Second European Zebrafish Principal Investigator Meeting in Karlsruhe, Germany, March 21-24, 2012. - 2013 - Zebrafish - 10 P119-23 - Cavodeassi F, Del Bene F, Fürthauer M, Grabher C, Herzog W, Lehtonen S, Linker C, Mercader N, Mikut R, Norton W, Strähle U, Tiso N, and Foulkes,NS

Endocytic regulation of notch signalling during development. - 2009 - Traffic - 10 P792-802 - Fürthauer M, and González-Gaitán,M

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Fürthauer Maximilian
Group Leader

2012 ARC Projet

2011 HFSP Career Development Award

2010 ATIP-Avenir

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    May 2014 - M. Furthauer Team
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    December 2010 - M. Furthauer Team
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