We study how individual cells acquire their fate in the context of a whole organism, usingDrosophila as a model system. Our research aims at deciphering the molecular mechanisms underlying selection, maintenance, self-renewal and/or differentiation of multipotent progenitor cells. Our research is centered around the role and regulation of Notch receptor signaling in specifying cell fates in simple lineages.

The adult sensory organ precursor cell (SOP) lineage is a simple and well-characterized lineage. We study how SOPs are singled out via lateral inhibition, a patterning process mediated by Notch, from groups of equipotent cells endowed with the potential to become SOPs. Once specified, each SOP follows a stereotyped series of four asymmetric divisions divides asymmetrically. At each division, binary fate decisions rely on the unequal segregation at mitosis of Numb, an endocytic adaptor protein that acts as an antagonist of Notch receptor signaling, and Neuralized, an E3 ubiquitin ligase that regulates the signaling activity of the Notch ligand Delta. We study how Numb and Neuralized are unequally inherited during asymmetric cell division. We investigate how Neuralized regulates the endocytosis signaling activity of Delta. We also study how the activity of Neuralized is controlled in time and space by inhibitors of the Bearded family. The role of ligand endocytosis in Notch receptor activation is further studied in the context of wing development. In this developmental setting, the E3 ubiquitin ligase Mindbomb1 regulates the endocytosis and signaling activity of the two Notch ligands, Delta and Serrate.

More recently, Notch signaling was shown to regulate tissue homeostasis in the adult gut by regulating self-renewal and differentiation of adult intestinal stem cell (ISC) lineage. ISCs divide to produce one self-renewed ISC and one post-mitotic cell that becomes an absorptive enterocyte or a secretory enteroendocrine cell. We currently investigate the molecular mechanisms underlying maintenance, self-renewal and/or differentiation of ISCs in adult flies.

Keywords: Drosophila, Notch, asymmetric cell division, stem cell, cell polarity, endocytosis, E3 ubiquitin ligase, lateral inhibition

1- A. J. Bardin and F. Schweisguth (2006), Bearded family members inhibit Neuralized-mediated endocytosis and signaling activity of Delta in Drosophila. Developmental Cell, 10, 245-55.

2- S. Petruk, Y. Sedkov, K. M. Riley, J. Hodgson, F. Schweisguth, S. Hirose, J. B. Jaynes, H. W. Brock and A. Mazo (2006) Transcription of bxd non-coding RNAs promoted by Trithorax represses Ubx in cis by transcriptional interference. Cell, 127, 1209-21

3- C. A. Smith, Kimberly M. L., Z. Rahmani, S. E. Dho, G. Brothers, Y. M. She, D. M. Berry, E. Bonneil, P. Thibault, F. Schweisguth, R. Le Borgne and C. J. McGlade (2007) aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb. EMBO Journal 26, 468-80.

4- J.-E. Gomes, M. S. Corado and F. Schweisguth (2009) Van Goghand frizzledact redundantly in the Drosophila sensory organ precursor cell to orient its asymmetric division. PLoSOne, 4(2) : e4485

5- S. Chanet, N. Vodovar, V. Mayau and F. Schweisguth (2009) Genome engineering-based analysis of Beardedfamily genes reveals both functional redundancy and a non-essential function in lateral inhibition inDrosophila. Genetics, 182, 1101-1108