Monday, 18th December 2017

Development and Regeneration

Morphogenesis and differentiation of vertebrate central nervous system

 

 Paola BovolentaGrupo 800x465 


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Paola Bovolenta

 

Research summary:

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Fig. 1. DiI (red) and DiO (green) labelling of cells located in the median anterior neural border of a chick embryo at gastrula stage. 

Fig. 2. Section of an E13 mouse embryo stained with antibodies that recognise differentiating Retinal Ganglion cells.

 


 

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Fig. 3. Zebrafish embryo with a chimera eye composed of host and EGFP-labelled donor cells. l, lens; r, retina.

Fig. 4. Flat-mount of a mouse embryonic retina electroporated with an EGFP plasmid to label developing retina ganglion cells

Fig. 5. Double staining of St21 medaka-fish embryo hybridised in toto with retinal (Rx3 red) and telencephalic (Fgf8, brown) specific markers.
 
 
 
 
 

Our research aims at defining the molecular mechanisms that control the early development of the vertebrate nervous system, mostly focusing on the visual system. We are particularly interested in those aspects that may help pinpointing the causes of congenital eye malformations or that are related to the onset of neurodegenerative diseases. Our main objectives are:

1) Understanding how patterning and morphogenesis of the forebrain are coordinated. There is evidence suggesting that the same signals that promote fate determination during forebrain formation are also driving forces for its morphogenesis. By exploiting the advantages of medaka, zebrafish and chick embryos, we are testing whether cell polarity remodelling and differential cohesive properties among the different forebrain territories are driving forces also for its morphogenesis. See also [Flor’s link] for further information.

2) Establishment of the transcriptional scaffold required for forebrain specification. Many regulators of eye development are expressed throughout the forebrain, raising the question of how is their activity diversified to lead to different patterning outcomes. Using multidisciplinary approaches in medaka, we have shown that graded expression levels and integration in different transcriptional networks are key mechanisms by which two transcription factors important in forebrain specification, Six3 and Six6, differentially contribute to forebrain patterning. Using similar approaches, in collaboration with researchers at the CABD (CSIC-UPO, Seville), we are now extending these studies to reconstruct the transcriptional scaffold required for forebrain specification.  

3) How does Shh signalling contribute to eye development and its connectivity? Shh signalling has a fundamental role in eye patterning and retinal ganglion cell (RGC) differentiation and we showed that it subsequently repurposed to control the growth of RGC axons. We wish now to determine how new components of the pathway, Cdon and Boc, regulate Shh response and diffusion in the visual system and define how Shh is transported and released from RGCs, establishing if the mechanism differs from that established for Drosophila epithelial cells (in collaboration with [link I. Guerrero]).

4) Analysis of the functional of Sfrp1 in neurodegenerative diseases. Sfrps are well-accepted Wnt signalling modulators but they can also work as regulators of metalloprotease activity. We have shown that Sfrp1/2 negatively modulate ADAM10, a metalloprotease with multiple substrates including the Amyloid Precursor Protein, N-Cadherin, axon guidance molecules and mediators of inflammation. Improper processing of some of these molecules is at the basis of neurodegenerative diseases such as Alzheimer’s disease or retinal dystrophies. We are currently analysing the impact of loss or gain of function Sfrp1 on the progression of these diseases, by using mouse genetics and functional approaches. As part of a collaborative effort with other members of the CiberEr we are also interested in understanding the origin of the neurodegenerative events that characterize Lafora Disease.


 

Latest publications:

  • Rodríguez, J., Esteve, P., Weinl, C., Ruiz, J.M., Fermin Y., Trousse, F., Dwivedy A, HoltC.E. and Bovolenta P. (2005)SFRP1 regulates the growth of retinal ganglion cell axons through the Fz2 receptor. Nat Neurosci. 8, 1301-1309. (News and Views 8, 1281-1282)
  • Sánchez-Camacho C. and Bovolenta P. (2008) Autonomous and non-autonomous Shh signalling mediate the in vivo growth and guidance of mouse retina ganglion cell axons. Development, 135, 3531-3540(cover caption article and Highlighs “In this issue”)
  • EsteveP., Sandonìs A., Cardozo M.,Malapeira J., Ibañez C.,Crespo I., Marcos S., Gonzalez-Garcia S., Toribio M.L., Arribas J., ShimonoA., Guerrero I.and Bovolenta P. (2011). Sfrps act as negative modulators of ADAM10 to regulate retinal neurogénesis. Nat. Neurosci. 14, 562-569. (Selected in The Faculty of 1000)
  • Beccari L., Conte I*, Cisneros E.* and Bovolenta P. (2012) Sox2-mediated differential activation of Six3.2 contributes to forebrain patterning. Development139, 151-164.
  • Sanchez-Arrones, L.*, Nieto-Lopez, F.*, Sanchez-Camacho, C., Carreres M.I., Herrera, E., Okada, A. and Bovolenta, P. (2013) Shh/Boc signaling is required for sustained generation of ipsilateral-projecting ganglion cells in the mouse retina. J. Neurosci. 33, 8596-8607. (Featured article). *Equally contributing.
  • Cardozo M., Sánchez-Arrones L., Sandonis A., Sánchez-Camacho C., Gestri G., Wilson SW, Guerrero, I. and Bovolenta P. (2014) Cdon acts as a Hh decoy receptor during proximal-distal patterning of the optic vesicle. Nat Commun. . 2014 Jul 8;5:4272.

 

Awards:

- Prize “Fundaluce”. 2009.
- FENS Comunication/Publication Commitee. 2009-present.
- Scientific Commitee, Telethon Combatti la Distrofia Muscolare e altre Malattie Genetiche, Italy 2006-2009.
- Selección “LS4–Neurosciences” European Research Council (ERC) Starting Grants. (2007-2010).

 

Doctoral Theses:

1. Los proteoglicanos como moduladores de guía axonal. Isabel Fernaud-Espinosa. Facultad de Ciencias, Universidad Complutense de Madrid. Octubre, 1996. Sobresaliente Cum Laude

2. Expresión, función e interacciones moleculares de Six6 y Six3 durante la morfogénesis del ojo en vertebrados. Javier López-Ríos Moreno. Facultad de Ciencias, Universidad Autónoma de Madrid. Julio, 2002. Sobresaliente Cum Laude

3. Modulación de la diferenciación y de la guía axonal en células ganglionares de la retina por SFRP1. Josana Rodríguez Sánchez. Facultad de Ciencias, Universidad Autónoma de Madrid. Febrero de 2005. - Sobresaliente Cum Laude

4. Estudio de la función de BMP7 en la formación del disco óptico. Julián Morcillo García. Facultad de Ciencias, Universidad Autónoma de Madrid. 16 Septiembre, 2008. Sobresaliente Cum Laude

5. Estudio de la función de Sfrp5 en el desarrollo del ojo y del techo óptico en el pez medaka. José Maria Ruiz. Facultad de Medicina, Universidad Autónoma de Madrid. Lectura en 17 de Abril de 2009. Sobresaliente Cum Laude.

6. Estudio del control transcripcional de los genes Six en vertebrados. Leonardo Beccari. Facultad de Ciencias, Universidad Autónoma de Madrid. Lectura 19 de Mayo 2011. Sobresaliente Cum Laude.

7. Generation of a medaka model for the Microphthalmia with linear skin lesion syndrome. Alessia Indrieri. European School of Molecular Medicine, Napoli, Italia. External co-supervisor (Supervisor: Prof. Brunella Franco). Lectura 14 Abril, 2011

8. Análisis de la función de Boc y Cdo durante el establecimiento de las conexiones retino-tectales en peces teleósteos. Marcos Cardozo. Facultad de Ciencias, Universidad Autónoma de Madrid. En desarrollo.

9. Función de Sfrp1 y Sfrp2 en el desarrollo de la corteza cerebral. Inmaculada Crespo. Facultad de Ciencias, Universidad Autónoma de Madrid. En desarrollo

10. Estudio de la función de la señalización mediada por Shh durante la formación de las vías visuales en vertebrados. Francisco Nieto. Facultad de Ciencias, Universidad Autónoma de Madrid. En desarrollo.

11. Caracterización del Sistema Nervioso Central en modelos animales de enfermedad de Lafora. Lara Trio Duran. Facultad de Ciencias, Universidad Autónoma de Madrid. Co-Dirección: Prof. S. Rodríguez de Córdoba, CIB-CSIC. En desarrollo.


Patents:

“Efecto mitógeno de Sonic hedgehog (Shh) sobre precursores de oligodendrocitos y su uso en enfermedades desmielinizantes”. nº 200600697.

“Método de diagnóstico de la enfermedad de Alzheimer que emplea Sfrp1 como biomarcador". nº 201130560.