Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly

Area of Science:

• Developmental biology
• Evolutionary biology
• Genetics

Background:

• Limb development relies on signaling centers like the zone of polarizing activity (ZPA) for axis patterning.
• The ZPA expresses sonic hedgehog (Shh) and its precise localization is crucial for normal limb formation.
• The mechanisms restricting ZPA and Shh expression to the posterior limb bud are not fully understood.

Purpose of the Study:

• To identify the gene responsible for the Strong's luxoid (lst) mouse mutation, which causes polydactyly due to ectopic anterior ZPA and Shh expression.
• To investigate the role of the candidate gene in limb patterning and the development of extra anterior digits.

Main Methods:

• Characterization of a new chlorambucil-induced deletion allele (lstAlb) to uncover the lst locus.
• Genetic mapping and complementation tests between lst alleles and an Alx4 gene-targeted allele.
• Molecular and biochemical analysis of lst alleles to identify mutations in the Alx4 gene.

Main Results:

• The Strong's luxoid (lst) gene was identified as the mouse Aristaless-like4 (Alx4) gene.
• Three lst mutant alleles represent loss-of-function mutations in Alx4.
• Alx4 haploinsufficiency is sufficient to cause polydactyly, indicating a critical threshold for Alx4 function.

Conclusions:

• Alx4 plays a crucial role in restricting polarizing activity and Shh expression to the anterior limb bud mesenchyme.
• Mutations in Alx4 underlie the Strong's luxoid polydactyly phenotype.
• Alx4 mutations may also be a cause of human polydactyly.