|Presenting Author(s)||Mohammad K. Hajihosseini|
|Abstract Title||The role of Fgf-Receptor signalling in outgrowth and patterning of the distal limb.|
|Full author List||Mohammad K. Hajihosseini, Clive Dickson and John K. Heath|
|Text of abstract||
Dominant-acting hypermorphic mutations in human FGF receptor-1 and -2 genes lead to two craniosynostosis syndromes: Pfeiffer and Apert, respectively, which, in addition to cranial defects carry distinct abnormalities of the distal limb - digit I in Pfeiffer and digits II-V in Apert syndrome.
These syndromes have not only provided genetic proof for sensitivity of the developing limbs to levels of FGFR signalling, but also highlighted specific roles for distinct FGFRs in distal limb development.
To understand the role of each receptor and dissect the cellular and
molecular mechanisms underlying the human abnormalities, we are studying the effects of two specific FgfR hypermorphic mutations in mice: (i) A Pfeiffer syndrome-type Pro252Arg mutation in FgfR1, introduced by BAC-transgenesis, and, (ii) An Apert syndrome-type ectopic up-regulation of FgfR2-IIIb in mesenchymal cells, brought about through Cre/LoxP-mediated deletion of FgfR2-IIIc (exon 9).
In contrast to man, mice heterozygous for either of these mutations lack limb defects. As homozygotes, however, BAC-FgfR1 mutant mice do develop specific abnormalities of digit I, suggesting the existence of threshold signalling differences between the two species. We have able to show that digit I defects in the FgfR1 mutant mice arise through perturbation of growth and patterning processes, as reflected by changes in the expression of genes such as Dkk1, Wnt5a and Hoxd-13, but not Shh.We would like to know if a similar threshold difference exists for FgfR2 signalling and identify the down-stream processes responsible for inducing digit II-V defects in Apert syndrome.
|Which session is your work most relevant to:||Human limb abnormalities|
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