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Gene Review

Arx  -  aristaless related homeobox

Mus musculus

Synonyms: Aristaless-related homeobox, Homeobox protein ARX

Disease relevance of Arx

  • Arx-deficient animals are born at the expected Mendelian frequency, but develop early-onset hypoglycemia, dehydration, and weakness, and die 2 d after birth [1].
  • Investigation of a critical region for an X-linked mental retardation (XLMR) locus led us to identify a novel Aristaless related homeobox gene (ARX ) [2].

High impact information on Arx

  • Male embryonic mice with mutations in the X-linked aristaless-related homeobox gene (Arx) developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain [3].
  • Our study indicates a requirement of Arx for alpha-cell fate acquisition and a repressive action on beta-and delta-cell destiny, which is exactly the opposite of the action of Pax4 in endocrine commitment [1].
  • Immunohistological analysis of pancreas from Arx mutants reveals an early-onset loss of mature endocrine alpha cells with a concomitant increase in beta-and delta-cell numbers, whereas islet morphology remains intact [1].
  • We have used gene targeting in mouse embryonic stem cells to generate Arx loss-of-function mice [1].
  • We propose that the antagonistic functions of Arx and Pax4 for proper islet cell specification are related to the pancreatic levels of the respective transcripts [1].

Biological context of Arx

  • A 1-Mb contig of BAC clones was assembled by using sequences flanking the transgene and revealed that the insertion lies close to Pola1 and Arx, a gene encoding a highly conserved homeobox protein known to be expressed in the developing forebrain of the mouse [4].
  • Data from Southern blots of normal and transgenic DNA demonstrated that a large segment of DNA encompassing Arx and including part of Pola1 was duplicated as a result of the transgene insertion [4].
  • A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death [5].

Anatomical context of Arx

  • The expression of Dlx1 and Arx in the presumptive ventral thalamus extended as far as ZLI and overlapped with that of Brx1 [6].
  • By using gain-of-function and loss-of-function assays in mouse and chicken embryos, we show that the Dlx genes have a conserved role in regulating the expression of Arx in the forebrain of vertebrates [7].
  • Expression of a novel aristaless related homeobox gene 'Arx' in the vertebrate telencephalon, diencephalon and floor plate [8].
  • Ectopic expression of Dlx genes with electroporation in brain slices from mouse embryos and in the neural tube of chick embryos shows that Dlx genes are sufficient to induce Arx ectopically [7].
  • Arx protein was expressed strongly in the interneurons and weakly in the radial glia of the olfactory bulb, but in neither the olfactory sensory neurons nor bulbar projection neurons [9].

Associations of Arx with chemical compounds


Regulatory relationships of Arx

  • Therefore, our results suggest evolutionarily conserved functions of Dlx genes in regulating Arx expression between Drosophila and vertebrates [7].
  • We found statistically significant overlap between the Arx and Dlx1/2 gene regulatory networks, which is in agreement with previous data, suggesting that Arx is downstream of Dlx1/2 in the subpallium, and we have identified the individual genes that are shared between these two networks [11].
  • We found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3, and Shox2 [11].
  • A genome-wide expression screen identified 84 genes whose expression was dysregulated in the subpallium in the absence of Arx [11].

Other interactions of Arx

  • Arx mutants lack ghrelin+ glucagon+ alpha-cells whereas Pax4 mutants develop an excess of these cells [12].
  • We report here crucial roles of the Arx homeobox gene in the developing olfactory system by analyzing its mutant phenotypes [9].
  • Genes containing E2F family transcription factor binding sites are enriched in subpallium of wildtype mice when compared to the subpallium of Arx mutants [11].

Analytical, diagnostic and therapeutic context of Arx

  • We generated a series of polyA expansions in Arx and expressed these in cell culture and brain slices [5].


  1. Opposing actions of Arx and Pax4 in endocrine pancreas development. Collombat, P., Mansouri, A., Hecksher-Sorensen, J., Serup, P., Krull, J., Gradwohl, G., Gruss, P. Genes Dev. (2003) [Pubmed]
  2. ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Bienvenu, T., Poirier, K., Friocourt, G., Bahi, N., Beaumont, D., Fauchereau, F., Ben Jeema, L., Zemni, R., Vinet, M.C., Francis, F., Couvert, P., Gomot, M., Moraine, C., van Bokhoven, H., Kalscheuer, V., Frints, S., Gecz, J., Ohzaki, K., Chaabouni, H., Fryns, J.P., Desportes, V., Beldjord, C., Chelly, J. Hum. Mol. Genet. (2002) [Pubmed]
  3. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Kitamura, K., Yanazawa, M., Sugiyama, N., Miura, H., Iizuka-Kogo, A., Kusaka, M., Omichi, K., Suzuki, R., Kato-Fukui, Y., Kamiirisa, K., Matsuo, M., Kamijo, S., Kasahara, M., Yoshioka, H., Ogata, T., Fukuda, T., Kondo, I., Kato, M., Dobyns, W.B., Yokoyama, M., Morohashi, K. Nat. Genet. (2002) [Pubmed]
  4. exma: an X-linked insertional mutation that disrupts forebrain and eye development. Cunningham, D., Xiao, Q., Chatterjee, A., Sulik, K., Juriloff, D., Elder, F., Harrison, W., Schuster, G., Overbeek, P.A., Herman, G.E. Mamm. Genome (2002) [Pubmed]
  5. A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. Nasrallah, I.M., Minarcik, J.C., Golden, J.A. J. Cell Biol. (2004) [Pubmed]
  6. Expression patterns of Brx1 (Rieg gene), Sonic hedgehog, Nkx2.2, Dlx1 and Arx during zona limitans intrathalamica and embryonic ventral lateral geniculate nuclear formation. Kitamura, K., Miura, H., Yanazawa, M., Miyashita, T., Kato, K. Mech. Dev. (1997) [Pubmed]
  7. The vertebrate ortholog of Aristaless is regulated by Dlx genes in the developing forebrain. Cobos, I., Broccoli, V., Rubenstein, J.L. J. Comp. Neurol. (2005) [Pubmed]
  8. Expression of a novel aristaless related homeobox gene 'Arx' in the vertebrate telencephalon, diencephalon and floor plate. Miura, H., Yanazawa, M., Kato, K., Kitamura, K. Mech. Dev. (1997) [Pubmed]
  9. Arx homeobox gene is essential for development of mouse olfactory system. Yoshihara, S., Omichi, K., Yanazawa, M., Kitamura, K., Yoshihara, Y. Development (2005) [Pubmed]
  10. Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons. Colombo, E., Galli, R., Cossu, G., Gécz, J., Broccoli, V. Dev. Dyn. (2004) [Pubmed]
  11. Identification of Arx transcriptional targets in the developing basal forebrain. Fulp, C.T., Cho, G., Marsh, E.D., Nasrallah, I.M., Labosky, P.A., Golden, J.A. Hum. Mol. Genet. (2008) [Pubmed]
  12. Genetic determinants of pancreatic epsilon-cell development. Heller, R.S., Jenny, M., Collombat, P., Mansouri, A., Tomasetto, C., Madsen, O.D., Mellitzer, G., Gradwohl, G., Serup, P. Dev. Biol. (2005) [Pubmed]
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