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Gene Review

Alx4  -  aristaless-like homeobox 4

Mus musculus

Synonyms: ALX-4, Aristaless-like 4, Homeobox protein aristaless-like 4, lst
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Disease relevance of Alx4


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


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


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


  1. Severe nasal clefting and abnormal embryonic apoptosis in Alx3/Alx4 double mutant mice. Beverdam, A., Brouwer, A., Reijnen, M., Korving, J., Meijlink, F. Development (2001) [Pubmed]
  2. Polydactyly and ectopic ZPA formation in Alx-4 mutant mice. Qu, S., Niswender, K.D., Ji, Q., van der Meer, R., Keeney, D., Magnuson, M.A., Wisdom, R. Development (1997) [Pubmed]
  3. Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome. Wu, Y.Q., Badano, J.L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L.G. Am. J. Hum. Genet. (2000) [Pubmed]
  4. Genetics of shoulder girdle formation: roles of Tbx15 and aristaless-like genes. Kuijper, S., Beverdam, A., Kroon, C., Brouwer, A., Candille, S., Barsh, G., Meijlink, F. Development (2005) [Pubmed]
  5. The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development. Takahashi, M., Tamura, K., Büscher, D., Masuya, H., Yonei-Tamura, S., Matsumoto, K., Naitoh-Matsuo, M., Takeuchi, J., Ogura, K., Shiroishi, T., Ogura, T., Belmonte, J.C. Development (1998) [Pubmed]
  6. Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4. Dunn, N.R., Winnier, G.E., Hargett, L.K., Schrick, J.J., Fogo, A.B., Hogan, B.L. Dev. Biol. (1997) [Pubmed]
  7. Function and regulation of Alx4 in limb development: complex genetic interactions with Gli3 and Shh. Kuijper, S., Feitsma, H., Sheth, R., Korving, J., Reijnen, M., Meijlink, F. Dev. Biol. (2005) [Pubmed]
  8. Alx4 and Msx2 play phenotypically similar and additive roles in skull vault differentiation. Antonopoulou, I., Mavrogiannis, L.A., Wilkie, A.O., Morriss-Kay, G.M. J. Anat. (2004) [Pubmed]
  9. Alx4 binding to LEF-1 regulates N-CAM promoter activity. Boras, K., Hamel, P.A. J. Biol. Chem. (2002) [Pubmed]
  10. Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4. Rice, R., Rice, D.P., Olsen, B.R., Thesleff, I. Dev. Biol. (2003) [Pubmed]
  11. Survey for paired-like homeodomain gene expression in the hypothalamus: restricted expression patterns of Rx, Alx4 and goosecoid. Asbreuk, C.H., van Schaick, H.S., Cox, J.J., Smidt, M.P., Burbach, J.P. Neuroscience (2002) [Pubmed]
  12. Alx-4, a transcriptional activator whose expression is restricted to sites of epithelial-mesenchymal interactions. Hudson, R., Taniguchi-Sidle, A., Boras, K., Wiggan, O., Hamel, P.A. Dev. Dyn. (1998) [Pubmed]
  13. Alx-4: cDNA cloning and characterization of a novel paired-type homeodomain protein. Qu, S., Li, L., Wisdom, R. Gene (1997) [Pubmed]
  14. Site-specific heterodimerization by paired class homeodomain proteins mediates selective transcriptional responses. Tucker, S.C., Wisdom, R. J. Biol. Chem. (1999) [Pubmed]
  15. Genetic interaction between Lef1 and Alx4 is required for early embryonic development. Boras-Granic, K., Grosschedl, R., Hamel, P.A. Int. J. Dev. Biol. (2006) [Pubmed]
  16. Genetic interaction of Gli3 and Alx4 during limb development. Panman, L., Drenth, T., Tewelscher, P., Zuniga, A., Zeller, R. Int. J. Dev. Biol. (2005) [Pubmed]
  17. Hoxb2 and hoxb4 act together to specify ventral body wall formation. Manley, N.R., Barrow, J.R., Zhang, T., Capecchi, M.R. Dev. Biol. (2001) [Pubmed]
  18. Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly. Qu, S., Tucker, S.C., Ehrlich, J.S., Levorse, J.M., Flaherty, L.A., Wisdom, R., Vogt, T.F. Development (1998) [Pubmed]
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