Gastrulation Brain Homeobox 2 (GBX2) is a homeobox gene involved in the normal development of rhombomeres 1-3 which is the mid/hindbrain region. This gene is a dosage dependent transcription factor involved in the regulation of proper expression of other genes. GBX2 expression occurs during gastrulation and continues to be expressed in the later stages of embryogenesis. During these different stages, GBX2 is responsible for several important processes. In the neural plate stage GBX2 is required in order for the anterior hindbrain precursors to survive and form correctly. Also at this stage in development GBX2 is required for the proper regulation of different gene expression needed for the early establishment of A/P patterning in the neural plate. In the early stages of brain morphogenesis GBX2 is required for both the normal development of the anterior hindbrain and the proper formation of the mid/hindbrain organizer. Because of the effects on the mid/hindbrain organizer, GBX2 is involved in the positioning of the expression domain for isthmicFGF8. Since this is a dosage dependent gene, the different amounts of gene present in certain location can cause different outcomes. FGF8 is affected by the different dosages in the location it is expressed. The absence of GBX2 causes FGF8 expression is shifted caudally and over expression of GBX2 causes FGF8 expression to be shifted rostrally. Not all of the rhombomeres GBX2 is expressed in require the same strictness of dose regulation. Of the three, rhombomere 2 has the most strict dose requirements.
Animal studies
Knockout of the GBX2 gene causes the failure of many structures to form, such as the isthmic nuclei, the cerebellum, motor nerve V and many other derivatives of rhombomeres 1-3. GBX2 gene knockout embryos will continue to develop and will reach full term pregnancy. The babies are born but if there is a lack of GBX2 expression all will die soon after birth.[4][5]
Knockdown of the gbx2 gene leads to a truncated anterior hindbrain as well as abnormal clusters of cell bodies in r2 and r3 which are associated with problems in cranial nerve V. It has been shown that any structures derived from r1-r3 will be adversely affected by mutations or deficiencies in gbx2. These structures include the aortic arch and right Subclavian artery which, when improperly developed, can lead to cardiovascular defects in addition to craniofacial defects from improper development of cranial nerve V.[6]
References
↑Kowenz-Leutz E, Herr P, Niss K, Leutz A (Oct 1997). "The homeobox gene GBX2, a target of the myb oncogene, mediates autocrine growth and monocyte differentiation". Cell. 91 (2): 185–95. doi:10.1016/S0092-8674(00)80401-8. PMID9346236.
↑Lin X, Swaroop A, Vaccarino FM, Murtha MT, Haas M, Ji X, Ruddle FH, Leckman JF (Feb 1996). "Characterization and sequence analysis of the human homeobox-containing gene GBX2". Genomics. 31 (3): 335–42. doi:10.1006/geno.1996.0056. PMID8838315.
↑Wassarman KM, Lewandoski M, Campbell K, Joyner AL, Rubenstein JL, Martinez S, Martin GR (Aug 1997). "Specification of the anterior hindbrain and establishment of a normal mid/hindbrain organizer is dependent on Gbx2 gene function". Development. 124 (15): 2923–34. PMID9247335.
↑Waters ST, Lewandoski M (May 2006). "A threshold requirement for Gbx2 levels in hindbrain development". Development. 133 (10): 1991–2000. doi:10.1242/dev.02364. PMID16651541.
↑Nakayama Y, Kikuta H, Kanai M, Yoshikawa K, Kawamura A, Kobayashi K, Wang Z, Khan A, Kawakami K, Yamasu K. "Gbx2 functions as a transcriptional repressor to regulate the specification and morphogenesis of the mid-hindbrain junction in a dosage- and stage-dependent manner". Mechanisms of Development. 130 (11–12): 532–52. doi:10.1016/j.mod.2013.07.004. PMID23933069.
Further reading
Burroughs-Garcia J, Sittaramane V, Chandrasekhar A, Waters ST (Apr 2011). "Evolutionarily conserved function of Gbx2 in anterior hindbrain development". Developmental Dynamics. 240 (4): 828–38. doi:10.1002/dvdy.22589. PMID21360792.
Gao AC, Lou W, Isaacs JT (Feb 2000). "Enhanced GBX2 expression stimulates growth of human prostate cancer cells via transcriptional up-regulation of the interleukin 6 gene". Clinical Cancer Research. 6 (2): 493–7. PMID10690529.
Gao AC, Lou W, Isaacs JT (Apr 1998). "Down-regulation of homeobox gene GBX2 expression inhibits human prostate cancer clonogenic ability and tumorigenicity". Cancer Research. 58 (7): 1391–4. PMID9537237.
Matsui T, Hirai M, Hirano M, Kurosawa Y (Dec 1993). "The HOX complex neighbored by the EVX gene, as well as two other homeobox-containing genes, the GBX-class and the EN-class, are located on the same chromosomes 2 and 7 in humans". FEBS Letters. 336 (1): 107–10. doi:10.1016/0014-5793(93)81620-F. PMID7903253.
