organisation - the Instituto Gulbenkian de Ciência

MOLECULAR
NEUROBIOLOGY
Diogo S. Castro Principal Investigator
PhD in Cell and Molecular Biology, Karolinska Institute, 2001
Post doctoral fellow, MRC National Institute for Medical Research, London, UK
Senior Investigator Scientist, MRC National Institute for Medical Research, London, UK
Principal Investigator at the IGC since 2010
The assembly of a functional nervous system depends on the coordinated
generation of neurons and glia cells from multipotent neural stem cells in the
developing embryo. The progression of this differentiation process is associated
and controlled by changes in gene expression programmes that need to
be very tightly regulated. For the moment we are mostly interested in understanding
the role played by various transcription factors, with a special focus
on bHLH proneural proteins, in neurogenesis. We aim at characterising their
transcriptional networks, as well as understanding the molecular mechanisms by
which such programmes are regulated, and how they contribute to the acquisition
of specific cellular phenotypes. In our work we take advantage of recently
developed genomic approaches that allow the characterisation of transcriptional
programmes at a genome wide level, complemented with more classical
methods to study gene expression, having the mouse embryo as a model
system.
GROUP MEMBERS
Alexandre Raposo (Post-doc, started in August 2011)
Vera Teixeira (Post-doc, started in May 2011)
Francisca Vasconcelos (PhD student)
Pedro Rosmaninho (PhD student, started in April 2011)
COLLABORATORS
François Guillemot (MRC National Institute for Medical Research, London, UK)
Stefan Momma (Johann Wolfgang Goethe University, Frankfurt, Germany)
Deolinda Lima (Faculdade de Medicina da Universidade do Porto,Portugal)
Vania Broccoli (San Raffaele Scientific Institute, Milan, Italy)
Carlos Parras (Hôpital de la Pitié-Salpêtrière, Paris, France)
FUNDING
Fundação para a Ciência e a Tecnologia (FCT), Portugal
Instituto Gulbenkian de Ciência (IGC), Portugal
PUBLIC ENGAGEMENT IN SCIENCE
Biology in Modern Times seminars for teachers, IGC, April
TRANSCRIPTIONAL CONTROL OF VERTEBRATE NEUROGENESIS
BY THE PRONEURAL FACTOR MASH1
Vertebrate neurogenesis is controlled, to a large extent, by basic helix-loophelix
proneural factors such as Mash1 (aka Ascl1). The use of Mash1 in reprogramming
protocols aiming at generating mature neurons from other cell types
stresses the importance of understanding the molecular mechanisms that underlie
its activity. Recently, we have performed the first genome wide characterisation
of a neurogenic programme downstream of Mash1, by the large
scale identification of its transcriptional targets. Strikingly, our results showed
that Mash1 directly controls both early (eg. cell fate commitment) and late (eg.
neurite outgrowth) steps of neurogenesis. This project aims at investigating
the epigenetic and transcriptional mechanisms that contribute to the temporal
regulation of neurogenesis by Mash1, by analysing the role played by the
chromatin landscape and interactions with other transcriptional networks that
operate in neural progenitors.
We have identified the zinc-finger transcription factor Myt1 as a direct target of
Mash1 in a neurogenic context. A transcriptional synergy between the two factors
in promoting differentiation suggests they may define an important feedforward-loop
at the onset of neurogenesis. The genome-wide characterisation
of Myt1 binding events in neural progenitors predict functional interactions with
other important transcriptional regulators, currently being investigated.
THE TRANSCRIPTIONAL NETWORK OF THE ZINC-FINGER FACTOR ZEB1
AND ITS FUNCTION IN NEURAL STEM/PROGENITOR CELLS
Current interest in neural stem cells derives from the prospect of using them
in brain repair strategies, but also to understand neurodevelopmental pathologies.
This will require, however, a significant improvement of our understanding
of the gene expression programmes associated with their maintenance and differentiation,
and how these are regulated. Recently, several lines of evidence
suggest a regulatory function for the zinc-finger transcription factor ZEB1, both
in embryonic neural stem/progenitor cells, and in human tumours of neural
origin. Here we propose to use a multidisciplinary approach, combining mouse
genetics and genomics, to characterise the function of ZEB1 in neural development.
Moreover, a comparison of the ZEB1 transcriptional programmes in human
foetal- and glioma-derived stem cells will be carried out, providing important
insights into ZEB1 function in tumour initiation and development.
We have begun to characterise the transcriptional programme downstream of
Zeb1 in neural stem/progenitor cells, having performed its genome-wide location
analysis, by chromatin immunoprecipitation followed by deep sequencing
(ChIP-seq).
HES6 PROMOTER.
Genome-wide location analysis by ChIP-seq shows binding of the transcription
factors Mash1, Hes1 and Myt1 to the proximal promoter region of the neurogenic
gene Hes6.
IGC ANNUAL REPORT ‘11
RESEARCH GROUPS
30