Saturday, 16th December 2017

Development and Regeneration

        Signaling mechanisms in development



 Lab414 Isabel Guerrero400px


Isabel Guerrero




Lab web link:

Research summary:

Secreted signaling molecules of the TGF-beta, Wnt, and Hedgehog (Hh) families have been shown to play essential roles in cell fate specification during development. In many developmental contexts, they act as morphogens that emanate from localized sources and form extracellular gradients, which differentially regulate cell fates in a concentration-dependent manner. Our group is studying the function of these morphogens during Drosophila development with higher input in the molecular and cellular mechanisms of Hh signaling. Hh is a molecule highly modified by lipids, which confer to Hh a high affinity for cell membranes. Despite these modifications, Hh protein can signal to cells distant from the source of its production. Presently, we are analyzing how Hh is released and transported through the extracellular matrix. The functional analysis of several proteins with a possible function in this process, such as Ihog, Boi, Dispatched, glypicans, and Shifted/DmWif, suggest that Hh is release through the basolateral side of polarized epithelia, with a previous recycling process from apical tobasolateral (Fig. 1). We are now working on the hipótesis that Hh is then transported in exovesicles attached to cellular extensions called "citonemas" (Fig. 2).




Ihog-RFP and Hh-GFP protein expression in the wing imaginal disc epithelium. Note that Hh-GFP is located in filopodia extensions, also called "cytonemes", and exovesicles in the wing imaginal disc.


Fig01-300  -------


Model for processing and release Hh.
A) In the producing cells Hh is translated, cleavage, lipid modified and externalized (red beads). B) Hh is then internalized and sorted to endosomes and to the apical recycling endosomes. In this process Hh probably interacts with Disp (blue discontinue line), Dlp, Dally, Boi (yellow background), and Ihog (green line). Hhis then transported to the basolateral membrane probably within multivesicular endosomes. C) These multivesicular endosomes fuse their membranes with the basolateral plasma membrane to form the cytonemes and release exovesicles. Hh is then transported in exovesicles to its target cells along cytonemes.




Relevant publications:

  • Callejo A, Bilioni A, Mollica E, Gorfinkiel N, Andrés G, Ibáñez C, Torroja C, Doglio L, Sierra J, Guerrero I. Dispatched mediates Hedgehog basolateral release to form the long-range morphogenetic gradient in the Drosophila wing disk epithelium. Proc Natl Acad Sci USA. (2011). Aug 2;108(31)12591-8. doi 10.1073pnas.1106881108. Epub 2011 Jun 20. Special feature article.
  • Sánchez-Hernández D, Sierra J, Ortigão-Farias JR,GuerreroI. The WIF domain of the human and Drosophila Wif-1 secreted factors confers specificity for Wnt or Hedgehog. Development. 2012 Oct;139(20):3849-58. Epub 2012 Sep 5. Erratum in: Development. 2013 Nov;140(22):4645. *Equally contributing.
  • Bilioni A*, Sánchez-Hernández D*, Callejo A, Gradilla AC, Ibáñez C, Mollica E, Carmen Rodríguez-Navas M, Simon E,GuerreroI.Balancing Hedgehog, a retention and release equilibrium given by Dally, Ihog, Boi and shifted/DmWif. Dev Biol. 2013 Apr 15;376(2):198-212. doi: 10.1016/j.ydbio.2012.12.013. Epub 2012 Dec 29.
  • Bischoff, M*., Gradilla, A.C.*, Seijo, I., Andrés G., Rodríguez-Navas, C., González- Méndez, L., and Guerrero, I. Cytonemes are required for the establishment of a normal Hedgehog morphogen gradient in Drosophila epithelia. Nature Cell Biol. (2013) Nov;15(11)1269-81. doi 10.1038ncb2856. Epub 2013 Oct 13. *Equally contributing.
  • Gradilla AC, González E, Seijo I, Andrés G, Bischoff M, González-Mendez L, Sánchez V, Callejo A, Ibáñez C, Guerra M, Ortigão-Farias JR, Sutherland JD, González M, Barrio R, Falcón-Pérez JM,Guerrero I. (2014) Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion. Nat Commun. Dec 4;5:5649. doi: 10.1038/ncomms6649.   


Doctoral Theses:

1. Papel del gen patched en el desarrollo embrionario e imaginal del Drosophila melanogaster Javier Capedvila Moya. Universidad: Autónoma de Madrid, Facultad de Ciencias, UAM. Abril 1995.

2. El papel del gen Distal-less en la identidad de los apèndices ventrales de Drosophila melanogaster. Nicole Gorfinkiel Haim, Universidad: Autónoma de Madrid, Facultad de Ciencias, Mayo 1998.

3. Estudio del papel de la vía de Señalización de Hedgehog en la determinación del patrón morfogenético del ala de Drosophila. : José Luis Mullor SanJosé. Universidad: Autónoma de Madrid. Facultad de Ciencias; UAM . Noviembre 1999.

4. Papel del gen patched en el mecanismo de señalización de Hedgehog. Carlos Torroja Fungairiño Universidad: Autónoma de Madrid, Facultad de Ciencias, UAM, Diciembre 2003.

5. Función del gen shf/Dwif en la vía de señalización de Hedgehog en Drosophila. Javier Sierra Isturiz. Universidad: Autónoma de Madrid. Facultad de Ciencias. Abril 2007.

6. Función de los genes lines y los genes de la familia Odd-Skipped en el desarrollo de los apéndices de Drosophila melanogaster.. Elvira Benítez de Gracia Universidad: Autónoma de Madrid. Facultad de Ciencias. Febrero 2008.

7. Papel de Ihog y Boi en la señalización de Hedgehog. David Sánchez Hernández Universidad: Autónoma de Madrid. Facultad de Ciencias. Enero 2014.

8. Control of two morphogenetic processes during Drosophila melanogaster metamorphosis: fusion of imaginal disc and ecdysis. Eleanor Simon Universidad: Autónoma de Madrid. Facultad de Ciencias. Noviembre 2016.