Disease relevance of Alx4

• Compound mutants of Alx3 and Alx4, however, show severe craniofacial abnormalities that are absent in Alx4 single mutants [1].
• Alx-4 is expressed in several populations of mesenchymal cells, including mesenchymal cells in the anterior limb bud, and mice homozygous for targeted disruption of the Alx-4 gene have multiple abnormalities, including preaxial polydactyly [2].

High impact information on Alx4

• Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome [3].
• We have studied the impact of Tbx15, Gli3, Alx4 and related genes on formation of the skeletal elements of the mouse shoulder and pelvic girdles [4].
• Alx3/Alx4 double mutant newborn mice have cleft nasal regions [1].
• Our data suggest the existence of a negative feedback loop between Alx-4 and Shh during vertebrate limb outgrowth [5].
• Chick Alx-4 displays an expression pattern complementary to that of shh, a mediator of polarizing activity in the limb bud [5].

Biological context of Alx4

• Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4 [6].
• 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 [7].
• Our observations suggest that Alx4 and Msx2 are partially functionally redundant, acting within a network of transcription factors and signalling events that regulate the rate of osteogenic proliferation and differentiation at a stage after the commitment of mesenchymal stem cells to osteogenesis [8].
• This interaction is mediated through a specific proline-rich domain in the N-terminal region of Alx4 and requires the DNA-binding domain (HMG-box) of LEF-1 [9].
• Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4 [10].

Anatomical context of Alx4

• Total lack of reporter expression in a Gli3-/- background confirms the existence of Gli3-dependent and -independent Alx4 expression in the limb bud [7].
• Furthermore, when expressed in primary mammary stromal cells, Alx4 decreases the expression of endogenous N-CAM protein [9].
• Furthermore, we found expression of Rx in the pineal gland, along with Alx4 [11].
• Alx-4-expressing tissues include osteoblast precursors of most bones, the dermal papilla of hair and whisker follicles, the dental papilla of teeth, and a subset of mesenchymal cells in pubescent mammary glands [12].
• The expression pattern of Alx-4 suggests that it may play a role in the patterning of structures derived from craniofacial mesenchyme, the first branchial arch, and the limb bud [13].

Associations of Alx4 with chemical compounds

• Here we compare and contrast the DNA binding properties of a glutamine 50 paired homeodomain protein, Alx4, and a lysine 50 paired homeodomain protein, Goosecoid [14].

Physical interactions of Alx4

• We determined previously that the mesenchymally restricted, paired-like homeodomain protein Aristaless-like 4 (Alx4) interacts with Lef1 and together alters promoter activity of candidate genes [15].

Regulatory relationships of Alx4

• The Gli3 and Alx4 transcriptional regulators are expressed in the anterior limb bud mesenchyme and their disruption in mice results in preaxial polydactyly [16].

Other interactions of Alx4

• Prior to this defect, both Alx3 and Alx4 were specifically down regulated in the most ventral part of the primary body wall in Hoxb4(PolII) mutants [17].
• We observed, as expected for authentic Alx4 expression, expansion of reporter construct expression in a Shh-/- background [7].
• The role of the aristaless-related homeobox gene Alx4 in antero-posterior (AP-) patterning of the developing vertebrate limb has remained somewhat elusive [7].
• In this study, we have localized the ossification defect in ch mutants to the calvarial mesenchyme, which lacks the expression of transcription factors Msx2 and Alx4 [10].
• We also show that BMP-induced expression of Msx2 and Alx4 requires Foxc1 [10].

Analytical, diagnostic and therapeutic context of Alx4

• In genetic crosses, the three lst mutant alleles fail to complement an Alx4 gene-targeted allele [18].
• We have analyzed the expression of Alx-4 during development by Northern blot and whole mount in situ hybridization [13].

References