Henry Roehl, PH.D.
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Zebra fish as a model for studies on the hereditary multiple exostosis.
Abstract 2005 MHE Conference
Malgorzata Wiweger, Aurélie Clément and Henry Roehl
Centre for Developmental Genetics, Department of Biomedical Science, University of
Sheffield, Firth Court, Sheffield S10 2TN, UK.
Zebra fish is an easy to maintain, small tropical fish with transparent embryos that develop outside
the mother’s body. Their short generation time (3-4 months), high fertility rate (hundreds of eggs
per week), rapid development (most organs develop within first 48 hours post fertilization) and
advanced genetic techniques (transgenics, forward and reverse genetics) make them an outstanding
model for biomedical research. Furthermore, development of their cartilaginous skeleton occurs by
similar mechanisms to that of humans, which means zebra fish are suitable as a model for studies on
human skeletal diseases.
Using forward genetic screens, hundreds of zebra fish mutations that affect cartilage morphogenesis
and/or differentiation have been identified. We positionally cloned two mutations in exostosin genes:
dackel (dak/ext2) and boxer (box/exlt3) (Lee et al., 2004, Neuron. 44: 947-960) and are currently
using these to study the development of exostoses. Homozygous dak/ext2 mutants show a similar
disorganization of cartilaginous skeleton to that seen in HME tumors i.e. chondrocytes, instead of
forming long stacks of flattened cells, form non-polarized clusters of rounded cells.
Cartilage formation and differentiation remains unaffected in dak/ext2 mutants, which suggest that
the dak/ext2 phenotype probably results from changes in cell division planes or/and cell movements.
In support, electron microscope observations verified the presence of abnormalities in the
cytoskeleton of dak/ext2 mutant chondrocytes. Furthermore, malformations of cartilage similar to
those seen in dak/ext2 are also present in another zebrafish mutant called pipetail (ppt/wnt5a) that
is involved in the non-canonical Wnt/Ca2+ planar polarity pathway.
Interestingly, both dak and ppt mutants show a significant delay in endochondrial ossification
whereas membranous bones are formed normally. The similarities between these two mutants
suggest Ext2 may act through non-canonical Wnt signaling.
In addition to the exostoses-like phenotype, dak/ext2 and box/exlt3 also share other developmental
defects (missorted retinotectal projections and malformed pectoral fins) and both of these mutants
have significantly reduced level of heparan sulfate proteoglycans (HSPGs). A third mutant, called
pinscher (pic), also has the mentioned above defects, suggesting that pic is in the same genetic
pathway.
We have recently positionally cloned pic and shown it does not belong the to exostosin gene family.
This strengthens the possibility that non-Ext1/Ext2-related cases of HME might be due to mutations
in other genes involved in the synthesis of HSPGs.
This work is supported by Wellcome Trust and Cancer Research UK.
Abstract 2005 MHE Conference
Malgorzata Wiweger, Aurélie Clément and Henry Roehl
Centre for Developmental Genetics, Department of Biomedical Science, University of
Sheffield, Firth Court, Sheffield S10 2TN, UK.
Zebra fish is an easy to maintain, small tropical fish with transparent embryos that develop outside
the mother’s body. Their short generation time (3-4 months), high fertility rate (hundreds of eggs
per week), rapid development (most organs develop within first 48 hours post fertilization) and
advanced genetic techniques (transgenics, forward and reverse genetics) make them an outstanding
model for biomedical research. Furthermore, development of their cartilaginous skeleton occurs by
similar mechanisms to that of humans, which means zebra fish are suitable as a model for studies on
human skeletal diseases.
Using forward genetic screens, hundreds of zebra fish mutations that affect cartilage morphogenesis
and/or differentiation have been identified. We positionally cloned two mutations in exostosin genes:
dackel (dak/ext2) and boxer (box/exlt3) (Lee et al., 2004, Neuron. 44: 947-960) and are currently
using these to study the development of exostoses. Homozygous dak/ext2 mutants show a similar
disorganization of cartilaginous skeleton to that seen in HME tumors i.e. chondrocytes, instead of
forming long stacks of flattened cells, form non-polarized clusters of rounded cells.
Cartilage formation and differentiation remains unaffected in dak/ext2 mutants, which suggest that
the dak/ext2 phenotype probably results from changes in cell division planes or/and cell movements.
In support, electron microscope observations verified the presence of abnormalities in the
cytoskeleton of dak/ext2 mutant chondrocytes. Furthermore, malformations of cartilage similar to
those seen in dak/ext2 are also present in another zebrafish mutant called pipetail (ppt/wnt5a) that
is involved in the non-canonical Wnt/Ca2+ planar polarity pathway.
Interestingly, both dak and ppt mutants show a significant delay in endochondrial ossification
whereas membranous bones are formed normally. The similarities between these two mutants
suggest Ext2 may act through non-canonical Wnt signaling.
In addition to the exostoses-like phenotype, dak/ext2 and box/exlt3 also share other developmental
defects (missorted retinotectal projections and malformed pectoral fins) and both of these mutants
have significantly reduced level of heparan sulfate proteoglycans (HSPGs). A third mutant, called
pinscher (pic), also has the mentioned above defects, suggesting that pic is in the same genetic
pathway.
We have recently positionally cloned pic and shown it does not belong the to exostosin gene family.
This strengthens the possibility that non-Ext1/Ext2-related cases of HME might be due to mutations
in other genes involved in the synthesis of HSPGs.
This work is supported by Wellcome Trust and Cancer Research UK.
The MHE Research Foundation would like to acknowledge and thank Dr. Karlstrom, Biology
Department, University of Massachusetts and Dr. Kane, Dept of Biology, University of Rochester
for the use of the zebrafish video.
Department, University of Massachusetts and Dr. Kane, Dept of Biology, University of Rochester
for the use of the zebrafish video.
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Research authored by Dr. Roehl
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List of Publications via PubMed
(NIH National Library of Medicine)
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List of Publications via PubMed
(NIH National Library of Medicine)
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Dr. Roehl's Research
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By the Health On the Net Foundation. Click here to verify.# HON Conduct 282463 and is linked on the NIH
National Library of Medicine, Directory of Health Organizations (SIS) website, as well as the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
The MHE Research Foundation is proud to be working with the EuroBoNeT consortium, a European Commission
granted Network of Excellence for studying the pathology and genetics of bone tumors.
granted Network of Excellence for studying the pathology and genetics of bone tumors.
Dr. Roehl serves on the Scientific and Medical Advisory Board of the MHE Research Foundation
Dr. Roehl presented his latest research during the 2007 Society For Glycobiology Conference held
in Boston.
Regulation of skeletal morphogenesis by sulphated proteoglycans in zebrafish
To read the abstract from this conference presentation Click Here
in Boston.
Regulation of skeletal morphogenesis by sulphated proteoglycans in zebrafish
To read the abstract from this conference presentation Click Here
