Serrate2 is disrupted in the mouse limb-development mutant syndactylism

Abstract

The mouse syndactylism (sm) mutation impairs some of the earliest aspects of limb development and leads to subsequent abnormalities in digit formation. In sm homozygotes, the apical ectodermal ridge (AER) is hyperplastic by embryonic day 10.5, leading to abnormal dorsoventral thickening of the limb bud, subsequent merging of the skeletal condensations that give rise to cartilage and bone in the digits, and eventual fusion of digits. The AER hyperplasia and its effect on early digital patterning distinguish sm from many other syndactylies that result from later failure of cell death in the interdigital areas. Here we use positional cloning to show that the gene mutated in sm mice encodes the putative Notch ligand Serrate. The results provide direct evidence that a Notch signalling pathway is involved in the earliest stages of limb-bud patterning and support the idea that an ancient genetic mechanism underlies both AER formation in vertebrates and wing-margin formation in flies. In addition to cloning the sm gene, we have mapped three modifiers of sm, for which we suggest possible candidate genes.

Jag2‐Notch1 signaling regulates oral epithelial differentiation and palate development

“…However, a spontaneous mis-sense mutation in the Jag2 gene, Jag2 sm , was shown to cause syndactyly in homozygous mutants, but no craniofacial defects were reported (Sidow et al, 1997). This finding raised the question whether the cleft palate phenotype in Jag2 ⌬DSL/⌬DSL mutants reflected a true function for Jag2 in craniofacial development.…”

“…Mice carrying the spontaneous Jag2 sm mutant allele (Sidow et al, 1997) were obtained from the Jackson Laboratory Mutant Mouse Resources and bred to C57BL/6J inbred mice to establish a colony. Heterozygous mice were identified by PCR genotyping with primers SM1 (5Ј-GCT GAC CAT CTC GGC CAG TG-3Ј) and SM2 (5Ј-GAC GCA CGT ACC GTC GAC AC-3Ј), which amplify a 263-bp product from both wild-type and mutant alleles.…”

Birth and death of cells in limb development: A mapping study

“…However, the INZ has a clear role in removing interdigital tissue, and when this removal is (partially) inhibited, either naturally as in duck (Pautou, 1974) and water hen (Hurle and Climent, 1987) or in spontaneous or induced mutants (i.e., Hinchliffe and Ede, 1973;Hinchliffe and Thorogood, 1974;Zou and Niswander, 1996;Sidow et al, 1997;Jiang et al, 1998;Francis et al, 2005;Lu et al, 2006), then interdigital webs survive into the definitive limb. Particularly interesting regarding mechanisms is the study by Lu et al (2006) showing that increased Fgf signaling from the mouse AER leads to absence of interdigital cell death without modification of the normal pattern of expression of BMPs.…”

“…Changes in the number of digits (polydactyly or oligodactyly) are frequent, as well as variable degrees of syndactyly. These malformations are frequently explained by modifications in the proliferation rates and/or cell death (Zakeri et al, 1994;Zou and Niswander, 1996;Sidow et al, 1997;Jiang et al, 1998;Sun et al, 2002;Grotewold and Rü ther, 2002;Francis et al, 2005;Johnson et al, 2005;Lu et al, 2006). Therefore, this study was stimulated by the need for a comprehensive description of the spatial and temporal distribution of cell death and cell proliferation during limb development.…”

Mind Bomb-2 Is an E3 Ligase for Notch Ligand

“…Indeed, all of these ligands have unique expression patterns, and the knock-out mice for each gene display a distinct phenotype. In parallel with the diversity of the ligands, more complex endocytic machinery might exist as well (12)(13)(14)(15)(16)(17)(18)(19)(20). In our search for the mouse Mind bomb homologue, we found one Mind bomb orthologue (Mib1) and one Mind bomb paralogue, Mind bomb-2 Mib2 (AY974090) skeletrophin (21).…”