|Drosophila Developmental Genetics - CNRS URA 2578|
|HEAD||Dr François SCHWEISGUTH / firstname.lastname@example.org|
|MEMBERS||Dr Allison Bardin / Soline Chanet / Dr Franck Coumailleau / Lydie Couturier / Dr David Del Alamo Rodriguez / Isabelle Dulieu / Sophie Hamel / Véronique Mayau / Dr M’hamed Khalil Mazouni / Carolina Perdigoto / Dr Nicolas Vodovar
Our research aims at understanding how individual cells acquire their fate during development using Drosophila as a model organisms. Our current studies address two main questions : how is cell-cell signaling mediated by the Notch receptor regulated in time and space to control binary cell fate decisions? and how do multipotent progenitor cells acquire and maintain their fate, generate differentiated progeny and self-renew?
Notch receptor activation in space and time
Notch receptors regulate many cell fate decisions and patterning events from worms to humans. Endocytosis and/or endosomal sorting of Notch and of its ligands Delta and Serrate have recently emerged as key regulatory steps in Notch signaling. The unit has previously shown that the E3 ubiquitin ligases Neuralized and Mindbomb1 regulate the internalization and/or endosomal sorting of the Notch ligands Delta and Serrate. We have carried out a molecular screen for partners of Neuralized and found that the activity of Neuralized is negatively regulated by proteins of the Bearded family. These proteins directly bind Neuralized and inhibit its activity. We have shown that genes of the Bearded Complexact to restrict the spatial domain of Delta signaling along the dorso-ventral axis of the early embryo and that this function is important to define the mesectoderm. We are currently investigating the potential role of the Beardedgenes in lateral inhibition. Additionally, structure-function studies are currently being performed to elucidate the molecular basis of the inhibition of Neuralized by proteins of the Bearded family. Finally, the function and regulation of Mindbomb is currently being investigated via the isolation of genetic interactors.
Specification and differentiation of multipotent progenitor cells
Multipotent progenitor cells play essential roles in the generation and homeostasis of many tissues. We are studying the molecular mechanisms regulating the specification, maintenance, self-renewal and/or differentiation of two types of multipotent progenitor cells, the Sensory Organ Precursor cells (SOPs) and the adult Intestinal Stem Cells (ISCs).
Each bristle sense organ is comprised of four different cells that are generated from a single SOP via a stereotyped series of asymmetric divisions. Specification of the SOP and of its progeny cells depends on Notch signaling. Two aspects have been studied. First, orientation of the SOP asymmetric division is regulated by planar cell polarity (PCP). Using live GFP imaging in genetic mosaics, we have found that components of two distinct PCP complexes act redundantly within the SOP to orient its polarity. Second, unequal segregation of Notch regulators, such as Numb and Neuralized, at mitosis regulates binary fate choices. Asymmetric localization of Numb in mitotic SOPs is in part regulated by the phosphorylation of Numb by aPKC. We have also investigated the potential role of phosphoinositides in this process and found an unexpected link between Partner of Numb and the localization of the PIP2-producing kinase Skittles.
Homeostasis of the adult gut relies on intestinal stem cells (ISCs) that produce two major types of cells: the absorptive enterocytes and the secretory enteroendocrine cells. Notch regulates the specification and differentiation of adult intestinal cells. We are currently studying the role of transcriptional inhibition of Notch target genes for ISC self-renewal.
Keywords: Drosophila, Notch, asymmetric cell division, stem cell, cell polarity, endocytosis, E3 ubiquitin ligase, lateral inhibition
C. Perdigoto, L. Gervais, E. Overstreet, J. Fischer, A. Guichet and F. Schweisguth (2008) Overexpression of Partner of Numb induces asymmetric distribution of the PI4P 5-kinase Skittles in mitotic sensory organ precursor cells in Drosophila. PLoSOne, 3(8): e3072. PMID: 18728778
Smith, C. A., Lau, K. M., Rahmani, Z., Dho, S. E., Brothers, G., She, Y. M., Berry, D. M., Bonneil, E., Thibault, P., Schweisguth, F., Le Borgne, R. and McGlade, C. J. (2007). aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb. Embo J 26, 468-480. PMID: 17203073
Bardin, A. J. and Schweisguth, F. (2006). Bearded family members inhibit Neuralized-mediated endocytosis and signaling activity of Delta in Drosophila. Dev Cell 10, 245-255. PMID: 16459303
R. Le Borgne, S. Remaud, S. Hamel and F. Schweisguth (2005), Two distinct E3 ubiquitin ligases have complementary functions in the regulation of Delta and Serrate signaling in Drosophila. PloS Biology, 3, e96. PMID: 15760269
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