Signal transduction and control of morphogenesis in Drosophila

The development of a multicellular organism is under a genetic program that integrates morphogenesis and proliferation and lead to the formation of different organs. It is well accepted that "signaling" molecules are key molecules that control the pattern formation during development.

Nevertheless, how gene expressions controlled by these signaling molecules are translated into cell behavior and morphogenetic process still needs to be resolved. We focus our studies on one of such molecule, the secreted cholesterol-modified Hedgehog (Hh) protein.

We use Drosophila as a paradigm for similar processes in vertebrates that are less accessible to genetic study. Our study should shed light on the link between dramatic developmental abnormalities observed in human embryos that are deficient for the Hh signal transduction pathway and the predisposition for brain and skin cancer appearance (Briscoe and Thérond, Dev. Cell 2005).

We use genetic and biochemical approaches to identify molecules that modulate the cellular responses to Hh because essential for the organization of the compartment borders in embryonic segments and in larvae imaginal discs. We identified a high molecular weight protein complex which governs proteolysis and access to the nucleus of the Ci/Gli transcription factor that mediates Hh signal (Robbins et al., Cell 1997; Ruel et al., Nature Cell Biology 2003). Moreover, our work highlighted the importance of the proteoglycans, component of the extra-cellular matrix, in the internalization of the ligand-receptor complex for Hh full- strength signaling (Gallet et al., Dev. Cell 2008). Recently we developed new tools to understand how the cytoplasmic complex responds to and transduces different levels of Hh signaling. We showed that the protein complex is differentially regulated, both through phosphorylation and change in sub-cellular localization, within Hh gradient. We propose that the change in the distribution of this protein complex in the cell, from the cytoplasm to the plasma membrane, promotes Ci/Gli activity necessary for high-level Hh signaling (Figure 1; Ranieri et al., Developmental Cell 2012).

In addition to being palmitoylated, Hh is the only metazoan protein known to possess a covalently-linked cholesterol moiety. We developed a new project dedicated to know how lipid-modified Hh is secreted and released from producing cells and how Hh morphogen spread in the Drosophila epitheliums (Thérond, Current Opinion in Cell Biology, 2012) . We showed that the cholesterol adduct is necessary for the controlled planar long range spreading of Hh. We showed that the release and spread of Hh into the hydrophilic environment of the extracellular space is contingent upon its assembly in large soluble multimers and glypican activity (Gallet et al., Dev. Cell , 2003 and Development 2006; Ayers et al., Dev. Cell 2010). We pioneered the concept that overall morphogen gradient such as Hh gradient is a cellular summation of pools secreted by different routes (apical and basolateral) and favor the existence of several carriers for transportation (Fig. 2; Ayers et al., Dev. Cell , 2010). We are currently isolating these different carriers and identifying the cellular machinery involved in Hh secretion. For this we developed cell biological approaches (life cell imaging) and genetic screens. For example, we have performed a genome-wide RNAi screen in Drosophila melanogaster cells to identify regulators of Hh secretion. We found that cholesterol-modified Hh secretion is strongly dependent on coat protein complex I (COPI) but not COPII vesicles, suggesting that cholesterol modification alters the movement of Hh through the early secretory pathway (Akin et al., Plos One 2012). Other candidate genes are studied by classical genetic tools.

 
Fig. 1
During development, the graded Hedgehog signal instructs differential cell fate. This study shows that low and high-magnitude Hedgehog signaling control differentially the sub-cellular localization and phosphorylation of the kinesin Costal2. It is proposed that dual phosphorylation of Costal2 facilitates high-level Hedgehog signaling through the control of Ci/Gli transcriptional activity (Ranieri et al., Dev. Cell 2012).


 

Fig. 2 In the epithelial field, morphogens like the Hedgehog peptides diffuse both apically and baso-laterally. Our study showed that the apical pool is involved in the long range activity of Hedgehog. We proposed that Hedgehog’s overall gradient is a composite of pools secreted by different routes (apical and basolateral). We also showed that the glypican Dally up-regulates apical Hh levels and that release of Dally by the PLC-like Notum promotes apical Hh long range activity.

 

Last publications

Switch of PKA substrates from Cubitus interruptus to Smoothened in the Hedgehog signalosome complex. - 2014 - Nature communications - 5 P5034 - Ranieri N, Thérond PP, and Ruel,L

The mechanisms of Hedgehog signalling and its roles in development and disease. - 2013 - Nature reviews. Molecular cell biology - 14 P416-29 - Briscoe J, and Thérond,PP

Distinct Phosphorylations on Kinesin Costal-2 Mediate Differential Hedgehog Signaling Strength. - 2012 - Dev Cell - Ranieri N, Ruel L, Gallet A, Raisin S, and Thérond,PP

Dally and Notum regulate the switch between low and high level Hedgehog pathway signalling. - 2012 - Development (Cambridge, England) - 139 P3168-79 - Ayers KL, Mteirek R, Cervantes A, Lavenant-Staccini L, Thérond PP, and Gallet,A

Release and transportation of Hedgehog molecules. - 2012 - Current opinion in cell biology - 24 P173-80 - Thérond,PP

Dynamic phosphorylation of the kinesin Costal-2 in vivo reveals requirement of fused kinase activity for all levels of hedgehog signalling. - 2010 - Dev Biol - 344 P119-28 - Raisin S, Ruel L, Ranieri N, Staccini-Lavenant L, and Thérond,PP

The long-range activity of Hedgehog is regulated in the apical extracellular space by the glypican Dally and the hydrolase Notum. - 2010 - Dev Cell - 18 P605-20 - Ayers KL, Gallet A, Staccini-Lavenant L, and Thérond,PP

Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling. - 2010 - Trends Cell Biol - 20 P287-98 - Ayers KL, and Thérond,PP

Variations in Hedgehog signaling: divergence and perpetuation in Sufu regulation of Gli. - 2009 - Genes Dev - 23 P1843-8 - Ruel L, and Thérond,PP

Tow (Target of Wingless), a novel repressor of the Hedgehog pathway in Drosophila. - 2009 - Dev Biol - 329 P280-93 - Ayers KL, Rodriguez R, Gallet A, Ruel L, and Thérond,P

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Thérond Pascal
Group Leader

2009 Prix Victor Noury Academie des Sciences

2001 Embo YIP

1998 ATIP CNRS

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Members Team
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   D Angelo Gisela
   Matusek Tamas
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    January 2016 - P. Therond Team
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    February 2013 - P. Therond Team
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