The sasquatch mouse : an enhanced limb

• Main Author: Heaney, Simon J. H.
• Published: University of Edinburgh 2003
• Subjects: 591.35
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.652286

The <i>sasquatch (Ssq) </i>mouse is a member of the hemimelia-luxate group of mutations, which display a variety of limb defects including preaxial polydactyly (extra digits). To identify the cis-acting elements implicated in the <i>Ssq </i>mutation a comparative sequence analysis of the <i>Lmbr1</i>genomic region in human, mouse and <i>Fugu </i>was implemented. Using the Vista and Pipmaker software packages, several highly conserved non-coding genomic sequences (CNSs) were identified as candidate regulatory elements. Two CNS regions that lie close to the <i>Ssq </i>insertion site were cloned into <i>LacZ </i>reporter constructs designed to assay for enhancer activity. Injection of these constructs into single cell mouse embryos to generate transgenic mice revealed that one of the CNS regions is capable of driving <i>LacZ </i>in an expression pattern identical to that of <i>Shh </i>in the developing limb bud. We believe that this CNS is an enhancer element responsible for driving <i>Shh </i>expression in the developing limb bud, and disruption of this element by the <i>Ssq </i>insertion is responsible for the phenotype observed in <i>Ssq </i>mice. The human genetic disease Preaxial Polydactyly (PPD) maps to a 450kb region syntenic to the <i>Ssq </i>insertion site. PPD is also a limb specific defect resulting in extra digits and no coding or splicing mutations have been found within the PPD critical region. <i>Ssq is </i>most likely the model for PPD confirming the likelihood that enhancer elements responsible for human genetic disease or variation could be acting over 100’s of kb within the human genome. Obviously this has important consequences for the mapping of human genetic disease and reaffirms the importance of mouse models in revealing underlying disease mechanisms.