1 April 1998 - 30 September 2002
Network Co-ordinator: Jim Smith
1 April 1998 - 30 September 2002
Network Co-ordinator: Jim Smith
The earliest step in the formation of
the vertebrate brain occurs during gastrula stages of development,
when a signal from axial mesoderm causes overlying ectodermal tissue
to form neural cell types rather than epidermis. This inductive event
was first described in amphibian embryos about 75 years ago (see ref.
1), but the molecular basis of neural induction remains unknown.
Recently, however, it has become clear that neural induction involves
overcoming the effects of inhibitors of neural development2
, notably the TGFB
family membes bone morphogenetic protein 2 (BMP-2) and bone
morphogenetic protein 4 (BMP-4)3-5. Two secreted factors
which inhibit BMP signalling, and thereby induce formation of neural
tissue, are noggin and chordin, both of which bind directly to BMP-2
or -4 (refs. 6, 7).
This proposal aims to understand in detail the mechanism by which
BMP's inhibit the formation of neural cell types and, conversely, how
noggin and chordin reverse this inhibition and induce neural tissue.
Briefly, we aim first to investigate the signalling ranges of BMP
famiily members and of their inhibitors; any true neural inducer
would be expected to act over a distance of several cell diameters.
We shall then study components of the BMP signal transduction
pathway, including BMP receptors and members of the Smad family, as
well as newly-discovered transcription factors which interact with
Smad proteins. BMP signalling activates the expression of genes such
as Xom8 and Mix.19, and we shall
investigate how regulation of these genes occurs. We intend also to
identify novel genes whose expresssion is regulated by BMP's, to
identify downstream targets of both these and of Xom and
Mix.1, and to study the consequences of blocking the functions
of these various gene products.
Components of the BMP signalling pathway have been extremely well
conserved through evolution10, so the lessons we learn
from our experiments in Xenopus and zebrafish will apply to
mammals and, of course, humans. The work is aimed primarily at coming
to an understanding of the earliest steps in the formation of the
vertebrate nervous system, an important end in itself. However, it is
likely also to shed light on other fundamental biological processes,
such as bone morphogenesis and repair. For example, disruption of the
noggin gene in mouse embryos by homologous recombination leads
to abnormalities in bone formation as well as in neural
differentiation (A. McMahon, personal communication). Furthermore,
BMP's are expressed in fractured bone and, when exogenously supplied,
accelerate bone repair11,12. Finally, Smad-4, a component
of the BMP-4 signalling pathway has recently been shown to encode a
tumour suppressor13, so our work could also shed light on
malignant proression, and may even lead to novel cancer therapeutic
strategies.
1. Spemann, H. Embryonic
Development and Induction (Garland Publishing, Inc. New
York and London, 1988, 1938). 2. Hemmati-Brivanlou, A. &
Melton, D. Cell 88, 13-17 (1997). 3. Hawley, S.H.B., et al.
Genes Dev. 9, 2923-2935 (1995). 4. Sasai, Y., Lu, B.,
Steinbeisser, H. & De Robertis, E.M. Nature
376, 333-336 (1995). 5. Wilson, P.A. &
Hemmati-Brivanlou, A. Nature 376 331-333
(1995). 6. Zimmerman, L.B., De Jesus
Escobar, J.M. & Harland, R.M. Cell 86,
599-606 (1996). 7. Piccolo, S., Sasai, Y., Lu,
B. & De Robertis, E.M. Cell 86, 589-598
(1996). 8. Ladher, R., Mohun, T.J.,
Smith, J.C. & Snape, A.M. Development 122,
2385-2394 (1996). 9. Mead, P.E., Brivanlous,
I.H., Kelley, C.M. & Zon, L.I. Nature 382,
357-360 (1996). 10. Derynck, R. & Zhang,
Y. Current Biology 6, 1226-1229
(1996). 11. Rosen, V. & Thies,
R.S. Trends Genet. 8, 97-102
(1992). 12. Wang, E.A. Trends
Biotechnol. 11, 379-383 (1993). 13. Hahn, S.A., et al.
Science 271, 350-353 (1996).
Division of Cellular
Biochemistry Imperial Cancer Research
Fund University of Leuven Institut de Biologie du
Developpement de Marseille Wellcome/CRC Institute
The Netherlands Cancer Institute
Plesmanlaan 121
1066 CX Amsterdam
The Netherlands
Tel: +31 20 5121979
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21 - 22 August
1998 Initial meeting 27 - 28 March 2000 Mid-term meeting 18 - 20 November
2000 Marseilles 12 - 13 November
2001 Amsterdam
Held at The Royal Society
UK
Host: Jim Smith
Held at the Imperial Cancer Research Fund
UK
Host: Caroline Hill
France
Host: Patrick Lemaire
The Netherlands
Host: Peter ten Dijke
Agenda
Photos
Monday 12 November
Welcome and introductory remarks (Jim Smith and Peter ten Dijke)
Round table introductions
14.30 Marie-Jose Goumans (Peter ten Dijke): TGF-beta and angiogenesis
15.00 Peter ten Dijke: Genetic screens to identify BMP antagonists
15.30 Break
15.45 Caroline Hill: The molecular basis for Smad2-transcription factor
Interactions
16.30 Tom van de Putte (Danny Huylebroeck): SIP1 (exon7) knockout mice
17.15 End of afternoon session
19.00 Dinner
Tuesday 13 November
9.00 Clare (Patrick Lemaire): Anterior neural induction in ascidians
9.30 Patrick Lemaire: Evolution of the function of brachyury
10.00 Fumiko Itoh (Peter ten Dijke): Function of SARA in TGF-beta signaling
10.30 Break
10.45 Sasha Korchinsky (Peter ten Dijke): BMPs in osteoblast differentiation
11.15 Huw Williams (Jim Smith): GFP-tagged TGF-betas
12.00 End of morning session
12.00-13.00 Lunch
13.00-14.00 Jim Smith: concluding remarks/round table discussion
List of Participants:
Jim Smith & Huw Williams
(Wellcome/CRC Inst. of Cancer and Dev. Biology, University of Cambridge)
Danny Huylebroeck, Leo van Grunsven, Kristin Verschueren & Tom van de Putte
(Dep. of Cell Growth, Differentiation and Development, University of Leuven)
Patrick Lemaire & Clare Hudson
(CNRS-INSERM-Universite de la Mediterranee-AP de Marseille)
Caroline Hill
(Lab. of Developmental Signalling, ICRF, London)
Peter ten Dijke, Fumiko Itoh, Marie-Jose Goumans, Franck Lebrin, Michiru Nishita, Sasha Korchinsky, Gudrun Valdimarsdottir & Midory Thorikay
(Netherlands Cancer Institute, Amsterdam)