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CDB Seminars
All welcome

Thursday 30 May at 1pm
Prof Hiroshi Kiyama, Nagoya University
Title: Collapse of homeostasis by prolonged stress - A model for Chronic Fatigue Syndrome and Fibromyalgia
Host: Prof David Whitmore
Venue: JZ Young Lecture Theatre

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Thursday 27 June at 1pm
Prof Richard Zigmond, Case Western Reserve University
Title: A new phenotype for the well-studied slow Wallerian degeneration mouse: A critical role in the conditioning lesion response for inflammation near axotomized neurons
Host: Prof David Whitmore
Venue: Anatomy G04 Gavin de Beer LT

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Dr Leslie Dale

We are interested in how the embryo of the frog Xenopus laevis develops from a fertilized egg into a swimming tadpole. Xenopus embryos have many advantages as a model for studying cell signalling during development: Large numbers of synchronously developing embryos are easily obtained and their large size and ease of culture means that they are amenable to micromanipulation and single cell injection. Workable transgenic protocols have been developed and there has been some success in inhibiting gene function with antisense technologies. As a consequence, studies on Xenopus embryos have made many important contributions to our understanding of vertebrate development.

Research

Our current research has focussed on the roles of two gene families in regulating early Xenopus development: the Tolloid family of metalloproteases and the large family of G-protein coupled receptors (GPCRs) .

Tolloid Metalloproteases

The Tolloid family of secreted metalloproteases are homologues of the Drosophila tolloid gene, which is required for dorsal-ventral patterning during the blastoderm stage of embryogenesis. In Xenopus, the three homologues that have so far been described are called BMP1 (a longer splice variant is usually called Tolloid), Xolloid, and Xolloid-related. All three genes are expressed during gastrulation where they appear to regulate the activity of BMP4, an extracellular signalling molecule that plays a central role in dorsal-ventral patterning. High concentrations of BMP4 specify ventral fates and low concentrations specify lateral fates, while dorsal fates require an absence of BMP. Tolloid metalloproteases regulate BMP4 signalling by cleaving Chordin, an inhibitory binding protein for BMP4 that is synthesised in the dorsal mesoderm of Xenopus gastrulae. Chordin that has been cleaved by Tolloids has a greatly reduced affinity for BMP4. While BMP1and Xolloid are widely distributed in Xenopus gastrulae, Xolloid-related is localised to ventral and lateral sectors of mesoderm suggesting that it could be the more important of the three in regulating Chordin. In addition to regulating Chordin, these proteases are also required to cleave components of the extracellular matrix, including the main fibrillar Collagens. The number of substrates known to be cleaved by these proteases continues to increase and a general theme is that they generate the mature protein from longer precursors.

 bmp4


BMP4 regulates dorsal-ventral patterning in Xenopus embryos. A) Control tadpole. B) Ventralised embryo injected with mRNA for BMP4 . C) Dorsalised embryo injected with mRNA for a dominant-negative BMP receptor. D) Partial duplicated dorsal axis caused by ventral injection of mRNA for a dominant-negative BMP receptor.

bmp1

Partial duplicated dorsal axis caused by ventral injection of mRNA for dominant-negative BMP1, which inhibits all three Tolloid metalloproteases

xlr1

Whole mount in situ hybridisations showing the expression pattern of xolloid-related in Xenopus embryos

p278st17

Whole mount in situ hybridisation showing p2y8 expression in Xenopus neurulae

G-Protein Coupled Receptors

The GPCR family is the largest family of cell-surface receptors, with thousands already described. In mice there are about 1000 GPCRs concerned with the sense of smell alone. They act as receptors for an enormous range of signals, including proteins, small peptides, amino acids, fatty acids, and nucleotides. All have a similar structure, a single polypeptide chain that threads back and forth across the lipid bilayer seven times, with an extracellular N-terminus and an intracellular C-terminus. They all activate trimeric GTP-binding proteins (G-proteins), relay molecules that activate a number of intracellular effector molecules (e.g. Ca2+ and cAMP).Despite their importance in adult physiology, relatively little is known about their roles in development. We have previously cloned a GPCR for extracellular nucleotides (e.g. ATP) that we have called P2Y8 and shown that it is localised to the developing neural plate. Transcripts are lost once the neural tube has formed, indicating that it has a role in the earliest phase of neural development. We have searched the Xenopus EST databases for GPCRs that are expressed during early developemnt, concentrating on receptors belonging to the P2Y subclass. At least four P2Y receptors are expressed in Xenopus gastrulae and we are currently characterising their roles in development.

Representative Publications:

Dale, Evans, Goodman (2002) Xolloid-related: A novel BMP1/Tolloid-related metalloprotease is expressed during early Xenopus development. Mech Dev 119: 177-190.

Dale, Jones (1999) BMP signalling in early Xenopus development. BioEssays 21:751-760.

Piccolo, Agius, Lu, Goodman, Dale, DeRobertis (1997) Cleavage of chordin by Xolloid metalloprotease suggests a role for proteolytic processing in the regulation of Spemann organizer activity. Cell 91: 407-416

Bogdonov, Dale, King, Whittock, Burnstock (1997) Early expression of a novel nucleotide receptor in the neural plate of Xenopus embryos. J Biol Chem 272: 12583-12590.

Links:

Xenbase

Lab members:

Dr Leslie Dale

 +44 (0)20 7679 3061
hristelle Devader (Research Assistant) +44 (0)20 7679 3367
Tim Geach (PhD Student) +44 (0)20 7679 3367

Page last modified on 07 sep 10 15:12 by Glenda Young