title: Function and regulation of Alx4 in limb development: complex genetic interactions with Gli3 and Shh.
abstract: The role of the aristaless-related homeobox gene Alx4 in antero-posterior (AP-) patterning of the developing vertebrate limb has remained somewhat elusive. Polydactyly of Alx4 mutant mice is known to be accompanied by ectopic anterior expression of genes like Shh, Fgf4 and 5'Hoxd. We reported previously that polydactyly in Alx4 mutant mice requires SHH signaling, but we now show that in early Alx4-/- limb buds the anterior ectopic expression of Fgf4 and Hoxd13, and therefore disruption of AP-patterning, occurs independently of SHH signaling. To better understand how Alx4 functions in the pathways that regulate AP-patterning, we also studied genomic regulatory sequences that are capable of directing expression of a reporter gene in a pattern corresponding to endogenous Alx4 expression in anterior limb bud mesenchyme. We observed, as expected for authentic Alx4 expression, expansion of reporter construct expression in a Shh-/- background. Total lack of reporter expression in a Gli3-/- background confirms the existence of Gli3-dependent and -independent Alx4 expression in the limb bud. Apparently, these two modules of Alx4 expression are linked to dissimilar functions.
authors.affiliation: Hubrecht Laboratory, The Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Kuijper
authors.forename: Harma
authors.initials: H
authors.lastname: Feitsma
authors.forename: Rushikesh
authors.initials: R
authors.lastname: Sheth
authors.forename: Jeroen
authors.initials: J
authors.lastname: Korving
authors.forename: Mark
authors.initials: M
authors.lastname: Reijnen
authors.forename: Frits
authors.initials: F
authors.lastname: Meijlink
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D017931:DNA Primers; D005121:Extremities / Q000196:embryology*; D023281:Genomics / Q000379:methods; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000378:metabolism*; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D000074290:Zinc Finger Protein Gli3; D001616:beta-Galactosidase
chemical_list: C109218:Alx4 protein, mouse; D017931:DNA Primers; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C465570:Shh protein, mouse; D015534:Trans-Activators; D000074290:Zinc Finger Protein Gli3; D001616:beta-Galactosidase