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Gene Review

Gbx2  -  gastrulation brain homeobox 2

Mus musculus

Synonyms: D130058E05Rik, Gastrulation and brain-specific homeobox protein 2, Gbx-2, Homeobox protein GBX-2, MMoxA, ...
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Disease relevance of Gbx2


High impact information on Gbx2

  • In mice, Otx2 is expressed in the forebrain and midbrain and Gbx2 is expressed in the anterior hindbrain, with a shared border at the level of the MHB organizer [2].
  • Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer [3].
  • In this study, we demonstrate that Wnt signaling is active in dorsal regions of the otic vesicle, where it functions to regulate the expression of genes (Dlx5/6 and Gbx2) necessary for vestibular morphogenesis [4].
  • This is further supported by our finding that inactivation of Gbx2, a homeobox-containing gene expressed in the presomitic mesoderm but not in the somites, produced Hox-like phenotypes in the axial skeleton without affecting Hox gene expression [5].
  • Changing requirements for Gbx2 in development of the cerebellum and maintenance of the mid/hindbrain organizer [6].
  • Gbx2 lineage-derived cells in medial ganglionic eminence (MGE) that undergo tangential migration exclusively give rise to almost all cholinergic interneurons in the striatum, whereas those undergoing radial migration mainly produce noncholinergic neurons in the basal forebrain. [7]

Biological context of Gbx2

  • In this study, we extend the phenotypic analysis of Gbx2 mutants by showing that Gbx2 is not only required for development of r1-3, but also for normal gene expression in r4-6 [8].
  • The mouse homeobox gene Gbx2 is first expressed throughout the posterior region of the embryo during gastrulation, and becomes restricted to rhombomeres 1-3 (r1-3) by embryonic day 8.5 (E8.5) [8].
  • Moreover, transcription factors En1 and Pax2 were also downregulated prior to the 4-somite stage, whereas Gbx2 downregulation occurred at the 4-somite stage [9].
  • We investigated the mouse Gbx2 locus by isolation and characterization of genomic clones and by physical localization to the genome [10].
  • The Gbx2 gene contained a single intron that separated the proposed functional protein domains [10].

Anatomical context of Gbx2

  • FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate [11].
  • Previous studies have shown that r1-3 do not develop in Gbx2 mutants and that there is an early caudal expansion of the midbrain gene Otx2 to the anterior border of r4 [8].
  • More strikingly, Fgf8b expression in more rostral brain regions appears to transform the midbrain and caudal forebrain into an anterior hindbrain fate through expansion of the Gbx2 domain and repression of Otx2 as early as the 7-somite stage [11].
  • Embryos deficient for both OTX2 and GBX2 proteins (hOtx1(2)/hOtx1(2); Gbx2(-/-)) show abnormal patterning of the anterior neural tissue, which is evident at the presomite-early somite stage prior to the onset of Fgf8 neuroectodermal expression [12].
  • Cortical axons (which do not express Gbx2) grew into the subpallium but did not enter the diencephalon [13].

Associations of Gbx2 with chemical compounds

  • As we demonstrate that the repression of Otx2 by retinoic acid is dependent on an induction of Gbx2 in the anterior brain, molecules other than retinoic acid must regulate the initial expression of Otx2 in vivo [14].

Regulatory relationships of Gbx2

  • Synergistic activity of Sef and Sprouty proteins in regulating the expression of Gbx2 in the mid-hindbrain region [15].
  • The expression compartment in the thalamus in which Slitrk6 was expressed was closely related to the Gbx2-expressing prosomere 2 [16].

Other interactions of Gbx2

  • Patterning and regionalisation of forebrain and midbrain were unaffected as revealed by the expression of diagnostic genes which are highly sensitive to reduction of OTX proteins, such as Fgf8, Pax2 and Gbx2 [17].
  • Furthermore, differentiation of neuroectoderm was accelerated as judged by the reduction of Oct4 expression and emergence of Sox1 and Gbx2 expression in the double mutant epiblast [18].
  • In Tbr1, Gbx2, Pax6 KO both thalamic and corticofugal projections fail to traverse the striatocortical junction [19].
  • Molecularly, the loss of the tectum is demonstrated by an expanded expression of Pax6, (the molecular determinant of posterior commissure), and a rostral shift of the territory of expression of Gbx2 and Otp (markers for the pons), towards the caudal diencephalon [20].
  • The Gbx-2 gene is expressed in four domains, two of which share sharp boundaries with the domains of the Dlx genes [21].

Analytical, diagnostic and therapeutic context of Gbx2


  1. Sequence and expression pattern of the Stra7 (Gbx-2) homeobox-containing gene induced by retinoic acid in P19 embryonal carcinoma cells. Bouillet, P., Chazaud, C., Oulad-Abdelghani, M., Dollé, P., Chambon, P. Dev. Dyn. (1995) [Pubmed]
  2. A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Millet, S., Campbell, K., Epstein, D.J., Losos, K., Harris, E., Joyner, A.L. Nature (1999) [Pubmed]
  3. Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. Joyner, A.L., Liu, A., Millet, S. Curr. Opin. Cell Biol. (2000) [Pubmed]
  4. Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Riccomagno, M.M., Takada, S., Epstein, D.J. Genes Dev. (2005) [Pubmed]
  5. Hox genes specify vertebral types in the presomitic mesoderm. Carapuço, M., Nóvoa, A., Bobola, N., Mallo, M. Genes Dev. (2005) [Pubmed]
  6. Changing requirements for Gbx2 in development of the cerebellum and maintenance of the mid/hindbrain organizer. Li, J.Y., Lao, Z., Joyner, A.L. Neuron (2002) [Pubmed]
  7. The mouse homeobox gene Gbx2 is required for the development of cholinergic interneurons in the striatum. Chen, L., Chatterjee, M., Li, J.Y. J. Neurosci. (2010) [Pubmed]
  8. New regulatory interactions and cellular responses in the isthmic organizer region revealed by altering Gbx2 expression. Li, J.Y., Lao, Z., Joyner, A.L. Development (2005) [Pubmed]
  9. Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice. Guo, C., Qiu, H.Y., Huang, Y., Chen, H., Yang, R.Q., Chen, S.D., Johnson, R.L., Chen, Z.F., Ding, Y.Q. Development (2007) [Pubmed]
  10. The mouse homeobox gene, Gbx2: genomic organization and expression in pluripotent cells in vitro and in vivo. Chapman, G., Remiszewski, J.L., Webb, G.C., Schulz, T.C., Bottema, C.D., Rathjen, P.D. Genomics (1997) [Pubmed]
  11. FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Liu, A., Losos, K., Joyner, A.L. Development (1999) [Pubmed]
  12. Regionalisation of anterior neuroectoderm and its competence in responding to forebrain and midbrain inducing activities depend on mutual antagonism between OTX2 and GBX2. Martinez-Barbera, J.P., Signore, M., Boyl, P.P., Puelles, E., Acampora, D., Gogoi, R., Schubert, F., Lumsden, A., Simeone, A. Development (2001) [Pubmed]
  13. Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: evidence that cortical and thalamic axons interact and guide each other. Hevner, R.F., Miyashita-Lin, E., Rubenstein, J.L. J. Comp. Neurol. (2002) [Pubmed]
  14. Otx2 and Gbx2 are required for refinement and not induction of mid-hindbrain gene expression. Li, J.Y., Joyner, A.L. Development (2001) [Pubmed]
  15. Synergistic activity of Sef and Sprouty proteins in regulating the expression of Gbx2 in the mid-hindbrain region. Lin, W., Jing, N., Basson, M.A., Dierich, A., Licht, J., Ang, S.L. Genesis (2005) [Pubmed]
  16. Slitrk6 expression profile in the mouse embryo and its relationship to that of Nlrr3. Aruga, J. Gene Expr. Patterns (2003) [Pubmed]
  17. OTX1 compensates for OTX2 requirement in regionalisation of anterior neuroectoderm. Acampora, D., Annino, A., Puelles, E., Alfano, I., Tuorto, F., Simeone, A. Gene Expr. Patterns (2003) [Pubmed]
  18. Complementary functions of Otx2 and Cripto in initial patterning of mouse epiblast. Kimura, C., Shen, M.M., Takeda, N., Aizawa, S., Matsuo, I. Dev. Biol. (2001) [Pubmed]
  19. Choreography of early thalamocortical development. Molnár, Z., Higashi, S., López-Bendito, G. Cereb. Cortex (2003) [Pubmed]
  20. Pax2/5 and Pax6 subdivide the early neural tube into three domains. Schwarz, M., Alvarez-Bolado, G., Dressler, G., Urbánek, P., Busslinger, M., Gruss, P. Mech. Dev. (1999) [Pubmed]
  21. Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12.5 mouse forebrain defines potential transverse and longitudinal segmental boundaries. Bulfone, A., Puelles, L., Porteus, M.H., Frohman, M.A., Martin, G.R., Rubenstein, J.L. J. Neurosci. (1993) [Pubmed]
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