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Presenting Author(s) Dylan Sweetman
Abstract Title The spalt genes in limb development and Townes-Brocks syndrome.
Full author List Dylan Sweetman, Terry Smith, Elizabeth Farrell & Andrea Münsterberg
Text of abstract The autosomal dominant condition Townes-Brocks syndrome (TBS) is characterised by various developmental defects including preaxial polydactyly. TBS is caused by premature stop codons in SALL1, a member of the spalt family of transcriptional repressors. Another member of the spalt family, SALL4, has also been implicated in Okihiro syndrome and some cases of Holt-Oram syndrome, both of which are associated with limb abnormalities. The SALL1 truncations in TBS were originally thought to produce non functional protein and the disease attributed to haploinsufficiency. In chick embryos two members of this family, csal1 and csal3, have been identified and are co-expressed in the developing limb. We have shown that full length csal1 and csal3 proteins can interact in vitro as can truncated proteins which mimic the mutations seen in TBS. This interaction is dependant on an N terminal glutamine rich region conserved in all spalt proteins so far characterised. Full length csal1 is expressed in the nucleus of cells, consistent with its role as a presumptive transcription factor, while csal3 is cytoplasmic. However, in the presence of csal3, csal1 is relocalised to the cytoplasm suggesting a possible role for csal3 as a negative regulator of csal1. "TBS like" N-terminal truncations of csal1 can also cause the mislocalisation of full length csal1. This suggests an alternative explanation for TBS where the truncated protein is able to act as a dominant negative and interfere with the function of other members of the family. We are also examining the role of tyrosine phosphorylation in the regulation of spalt function and subcellular localisation.
Which session is your work most relevant to: Limb patterning