title: Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly.
abstract: Mutations that affect vertebrate limb development provide insight into pattern formation, evolutionary biology and human birth defects. Patterning of the limb axes depends on several interacting signaling centers; one of these, the zone of polarizing activity (ZPA), comprises a group of mesenchymal cells along the posterior aspect of the limb bud that express sonic hedgehog (Shh) and plays a key role in patterning the anterior-posterior (AP) axis. The mechanisms by which the ZPA and Shh expression are confined to the posterior aspect of the limb bud mesenchyme are not well understood. The polydactylous mouse mutant Strong's luxoid (lst) exhibits an ectopic anterior ZPA and expression of Shh that results in the formation of extra anterior digits. Here we describe a new chlorambucil-induced deletion allele, lstAlb, that uncovers the lst locus. Integration of the lst genetic and physical maps suggested the mouse Aristaless-like4 (Alx4) gene, which encodes a paired-type homeodomain protein that plays a role in limb patterning, as a strong molecular candidate for the Strong's luxoid gene. In genetic crosses, the three lst mutant alleles fail to complement an Alx4 gene-targeted allele. Molecular and biochemical characterization of the three lst alleles reveal mutations of the Alx4 gene that result in loss of function. Alx4 haploinsufficiency and the importance of strain-specific modifiers leading to polydactyly are indicative of a critical threshold requirement for Alx4 in a genetic program operating to restrict polarizing activity and Shh expression in the anterior mesenchyme of the limb bud, and suggest that mutations in Alx4 may also underlie human polydactyly.
authors.affiliation: Departments of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: S
authors.initials: S
authors.lastname: Qu
authors.forename: S C
authors.initials: SC
authors.lastname: Tucker
authors.forename: J S
authors.initials: JS
authors.lastname: Ehrlich
authors.forename: J M
authors.initials: JM
authors.lastname: Levorse
authors.forename: L A
authors.initials: LA
authors.lastname: Flaherty
authors.forename: R
authors.initials: R
authors.lastname: Wisdom
authors.forename: T F
authors.initials: TF
authors.lastname: Vogt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D002699:Chlorambucil / Q000494:pharmacology; D002874:Chromosome Mapping; D029721:Drosophila Proteins; D005121:Extremities / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000737:chemistry*; D019476:Insect Proteins / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology; D016296:Mutagenesis / Q000235:genetics; D017689:Polydactyly / Q000235:genetics*; D011506:Proteins / Q000502:physiology; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics; D015534:Trans-Activators
chemical_list: C109218:Alx4 protein, mouse; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D019476:Insect Proteins; D011506:Proteins; C509239:SHH protein, human; D015534:Trans-Activators; C079410:al protein, Drosophila; D002699:Chlorambucil