Polarity, division and morphogenesis

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Group leader: Yohanns Bellaïche
Yohanns Bellaïche Team

Keywords

cell polarity, division, mitotic spindle orientation, asymmetric cell division, morphogenesis

Plain english

Our research group aims at understanding: 1) How cell fate diversity is generated during development? How organs acquire their shape? To address these two questions, we are using the Drosophila fruit fly model where we can easily study mutants affecting cell fate specification or organ shape. Hence, we could identify the genes necessary for cell fate and tissue shape determination. Finally we are implementing tools from modern physic to better understand the dynamic and the mechanic of tissue during development.


Cell polarity is fundamental to many aspects of cell and developmental biology and it is implicated in differentiation, proliferation and morphogenesis in both unicellular and multi-cellular organisms. Furthermore, loss of cell polarisation is a property common to cancer cells.

We are studying the mechanisms regulating cell polarity during two key embryonic development processes in Drosophila: asymmetric cell division and epithelial tissue morphogenesis. The study of asymmetric division provides an understanding of the manner in which distinct cells are produced during development and of how stem cells are maintained during adult life. The study of epithelial morphogenesis provides an understanding of how cells and tissues organise to form functional organs.

In order to gain an understanding of the fundamental processes, our team is currently using two complementary approaches:

1. We combine the use of genetic tools with cutting edge optical microscopy to analyse cell polarisation mechanisms during division and tissue dynamics (Film 1 and Film 2).

2. We use innovative inter-disciplinary methodologies in the fields of cell and developmental biology. On the one hand, the imaging of individual molecules in cells in order to better understand how molecules move within cells (Film 3).

On the other hand, we describe the development of epithelial cells in a quantitative manner using new mathematical tools used to quantify the geometric and topological changes in a group of cells affecting tissue development.

The underlying cell polarisation mechanisms are maintained throughout evolution. These experiments thus improve our knowledge for all animals. Finally, as loss of cell polarisation is a property common to cancer cells, our work shall lead to improved understanding of the cell processes affected during tumour diseases.

 




Key publications

  • Year of publication : 2012

  • During development, epithelial tissues undergo extensive morphogenesis based on coordinated changes of cell shape and position over time. Continuum mechanics describes tissue mechanical state and shape changes in terms of strain and stress. It accounts for individual cell properties using only a few spatially averaged material parameters. To determine the mechanical state and parameters in the Drosophila pupa dorsal thorax epithelium, we severed in vivo the adherens junctions around a disc-shaped domain comprising typically a hundred cells. This enabled a direct measurement of the strain along different orientations at once. The amplitude and the anisotropy of the strain increased during development. We also measured the stress-to-viscosity ratio and similarly found an increase in amplitude and anisotropy. The relaxation time was of the order of 10 s. We propose a space-time, continuous model of the relaxation. Good agreement with experimental data validates the description of the epithelial domain as a continuous, linear, visco-elastic material. We discuss the relevant time and length scales. Another material parameter, the ratio of external friction to internal viscosity, is estimated by fitting the initial velocity profile. Together, our results contribute to quantify forces and displacements, and their time evolution, during morphogenesis.
  • During animal development, several planar cell polarity (PCP) pathways control tissue shape by coordinating collective cell behavior. Here, we characterize by means of multiscale imaging epithelium morphogenesis in the Drosophila dorsal thorax and show how the Fat/Dachsous/Four-jointed PCP pathway controls morphogenesis. We found that the proto-cadherin Dachsous is polarized within a domain of its tissue-wide expression gradient. Furthermore, Dachsous polarizes the myosin Dachs, which in turn promotes anisotropy of junction tension. By combining physical modeling with quantitative image analyses, we determined that this tension anisotropy defines the pattern of local tissue contraction that contributes to shaping the epithelium mainly via oriented cell rearrangements. Our results establish how tissue planar polarization coordinates the local changes of cell mechanical properties to control tissue morphogenesis.
  • Year of publication : 2010

  • The Frizzled receptor and Dishevelled effector regulate mitotic spindle orientation in both vertebrates and invertebrates, but how Dishevelled orients the mitotic spindle is unknown. Using the Drosophila S2 cell "induced polarity" system, we find that Dishevelled cortical polarity is sufficient to orient the spindle and that Dishevelled's DEP domain mediates this function. This domain binds a C-terminal domain of Mud (the Drosophila NuMA ortholog), and Mud is required for Dishevelled-mediated spindle orientation. In Drosophila, Frizzled-Dishevelled planar cell polarity (PCP) orients the sensory organ precursor (pI) spindle along the anterior-posterior axis. We show that Dishevelled and Mud colocalize at the posterior cortex of pI, Mud localization at the posterior cortex requires Dsh, and Mud loss-of-function randomizes spindle orientation. During zebrafish gastrulation, the Wnt11-Frizzled-Dishevelled PCP pathway orients spindles along the animal-vegetal axis, and reducing NuMA levels disrupts spindle orientation. Overall, we describe a Frizzled-Dishevelled-NuMA pathway that orients division from Drosophila to vertebrates.
  • Year of publication : 2009

  • Stem cells generate self-renewing and differentiating progeny over many rounds of asymmetric divisions. How stem cell growth rate and size are maintained over time remains unknown. We isolated mutations in a Drosophila melanogaster gene, wicked (wcd), which induce premature differentiation of germline stem cells (GSCs). Wcd is a member of the U3 snoRNP complex required for pre-ribosomal RNA maturation. This general function of Wcd contrasts with its specific requirement for GSC self-renewal. However, live imaging of GSCs within their niche revealed a pool of Wcd-forming particles that segregate asymmetrically into the GSCs on mitosis, independently of the Dpp signal sent by the niche. A fraction of Wcd also segregated asymmetrically in dividing larval neural stem cells (NSCs). In the absence of Wcd, NSCs became smaller and produced fewer neurons. Our results show that regulation of ribosome synthesis is a crucial parameter for stem cell maintenance and function.