title: 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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. arend@genome.wi.mit.edu
authors.forename: A
authors.initials: A
authors.lastname: Sidow
authors.forename: M S
authors.initials: MS
authors.lastname: Bulotsky
authors.forename: A W
authors.initials: AW
authors.lastname: Kerrebrock
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: M J
authors.initials: MJ
authors.lastname: Daly
authors.forename: M P
authors.initials: MP
authors.lastname: Reeve
authors.forename: T L
authors.initials: TL
authors.lastname: Hawkins
authors.forename: B W
authors.initials: BW
authors.lastname: Birren
authors.forename: R
authors.initials: R
authors.lastname: Jaenisch
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004475:Ectoderm / Q000378:metabolism; D005091:Exons; D005121:Extremities / Q000196:embryology; D005260:Female; D015870:Gene Expression; D008040:Genetic Linkage; D005998:Glycine / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D013576:Syndactyly / Q000196:embryology / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C108635:serrate2 protein, mouse; D005998:Glycine