You are here:
The Hemimelic extra toes mouse mutant: Historical perspective on unraveling mechanisms of dysmorphogenesis
KNUDSEN, T. B. AND D. M. KOCHHAR. The Hemimelic extra toes mouse mutant: Historical perspective on unraveling mechanisms of dysmorphogenesis. Birth Defects Research, Part C: Embryo Today: Reviews. John Wiley & Sons, Ltd., Indianapolis, IN, 90(2):155-162, (2010).
This review for the special issue “Teratology - past, present and future” is written to honor the 50th anniversary of the Teratology Society, and in particular to celebrate one aspect of the society‟s mission: “… to promote research and the exchange of ideas and research results that reveal the causes, improve the diagnosis and treatment, and prevent the occurrence of abnormal development and birth defects.” The article is dedicated to those who devoted all or most of their professional career to advancing the Principles of Teratology, to identifying etiologies and unraveling mechanisms through scientific research, and to the next generation of young researchers that may continue to advance collective wisdom of the discipline through scientific knowledge and technological achievement.
Hemimelic extra toes (Hx) arose spontaneously as a dominant mutation in B10.D2/nSnJ mice in 1967. It specifically affects the appendicular skeleton, causing variable foreshortening of the tibia (radius) and preaxial polydactylism. Early anatomical studies revealed anterior overgrowth of the autopod, with decreased apoptosis and increased mitosis in the anterior apical ectodermal ridge (AER) and underlying mesenchyme; overextension of apoptosis in the central zeugopod accounted for hemimelia. The Hx mutant phenotype was coarsely mapped to mouse chromosome (Chr) 5, closely linked to engrailed-2 (En2) and Sonic hedgehog (Shh). This region is syntenic to human Chr 7q36 that harbors several dominant mutations affecting the hand. High resolution genome mapping identified the Hx mutation as a GA base pair transition within intron 5 of the murine Limbr1 locus. The critical effect is on a multifunctional conserved regulatory element that acts as a limb-specific, long distance cis-acting enhancer of Shh expression. As such, the Hx mutant phenotype results from ectopic Shh signals at the anterior margin of the limb-bud that directly or indirectly alter FGF4 signaling from the AER. Given significant advances in understanding of embryonic development in general and limb development in particular, this review article reveals how research that once attracted interest of teratologists has advanced across the decades to pinpoint a critical molecular lesion and reveal a potential mechanism of a specific malformation that is found commonly in experimental teratology.