Alternative titles; symbols
HGNC Approved Gene Symbol: HOXB2
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:48,542,655-48,545,109 (from NCBI)
The HOX genes, distributed into 4 gene clusters, encode homeodomain-type transcription factors that work in concert to regionalize the developing embryo along its major axes. Expression of HOX genes within each cluster is controlled temporally and spatially so that the 3-prime gene is activated prior to and in a more anterior region of the embryo than its 5-prime neighbor (summary by Barrow and Capecchi, 1996).
The mammalian HOX gene family contains 38 homeobox gene members located in 4 independent complexes named HOXA, HOXB, HOXC, and HOXD (or, in keeping with the nomenclature of the Human Gene Mapping Workshops, HOX1, HOX2, HOX3, and HOX4, respectively). These 4 clusters of genes are located on chromosomes 7, 17, 12, and 2, respectively. These genes are expressed during embryonic development, at which time they have a determinant role in the body plan organization. They have also been implicated in the regulation of hematopoietic cell growth and differentiation. Genes of the HOXB (or HOX2) complex are expressed specifically in erythromegakaryocytic cell lines, and some of them are expressed only in hematopoietic progenitors. Vieille-Grosjean and Huber (1995) isolated the 5-prime flanking sequence of the HOXB2 (HOX2H) gene and characterized a promoter fragment extending 323 bp upstream from the transcriptional start site. In transfection experiments, this promoter region was sufficient to direct the tissue-specific expression of HOXB2 in an erythroid cell line. Through analysis of point mutations, Vieille-Grosjean and Huber (1995) identified a potential GATA-binding site in the promoter that is essential for its transcriptional activity. They suggested the existence of a regulatory hierarchy in which GATA1 (305371) is upstream of the HOXB2 gene in erythroid cells.
To investigate the functions of paralogous HOX genes, Pollock et al. (1995) compared the phenotypic consequences of altering the embryonic patterns of expression of Hoxb8 and Hoxc8 in transgenic mice. Altering expression of the 2 paralogs in the axial skeletons of newborns resulted in an array of common transformations as well as morphologic changes unique to each gene. Divergence of function of the 2 paralogs was clearly evident in costal derivatives, where increased expression of the 2 genes affected opposite ends of the ribs. Many of the morphologic consequences of expanding the mesodermal domain and magnitude of expression of either gene were atavistic, inducing the transformation of axial skeleton structures from a modern to an earlier evolutionary form. Pollock et al. (1995) proposed that regional specialization of the vertebral column has been driven by regionalization of HOX gene function and that a major aspect of this evolutionary progression may have been restriction of HOX gene expression.
Zhai et al. (2005) reported that HOXB2 interacted with the G93A (147450.0008)-mutant SOD1 (147450) in a yeast 2-hybrid screen. HOXB2 coprecipitated and colocalized with mutant SOD1 in neuronal cell lines, as well as in brain and spinal cord of G93A-mutant SOD1 transgenic mice. In motor neuron-like NSC-34 cells, overexpression of HOXB2 or its homeodomain decreased the insolubility of mutant SOD1 and inhibited G93A or G86R (see 147450.0006)-mutant SOD1-induced neuronal cell death. In human and mouse tissues, expression of HOXB2 persisted in adult spinal cord and was primarily localized in nuclei of motor neurons. In G93A transgenic mice, HOXB2 colocalized with mutant SOD1 and was redistributed to perikarya and proximal neurites of motor neurons. There was progressive accumulation of HOXB2 and mutant SOD1 as punctate inclusions in the neuropil surrounding motor neurons. Zhai et al. (2005) concluded that HOXB2 interacts with mutant SOD1 in motor neurons of G93A-mutant SOD1 transgenic mice, and suggested that this interaction may modulate the neurotoxicity of mutant SOD1.
To investigate the functions of group 2 homeobox genes in early neurogenesis, Davenne et al. (1999) analyzed single and double Hoxa2 (604685) and Hoxb2 mutants. Morphologic analysis showed that the normal number of segments form in the mutants, but that the boundaries between rhombomere segments are incorrectly generated. Math3 expression is reduced in rhombomere (r) 4 in Hoxb2 mutants. Whereas Hoxa2 appears to control the distribution of subsets of neuronal precursors in r2 and r3, Hoxb2 appears to function mainly in r4. In addition, Hoxa2 controls development in alar and 'dorsal' basal plates of r2 and r3, whereas Hoxb2 is essential for motor neuron development in the 'ventral' basal plate of r4. In situ hybridization studies identified this pattern of changes in molecular marker expression with probes for Mash1 (100790), ngn2 (606624), and Phox2b (603851).
Barrow and Capecchi (1996) generated mice with a disruption in Hoxb2 by gene targeting. They obtained Hoxb2 -/- mice at a mendelian ratio, but the majority died prior to week 3, likely due to severe malformation of the sternum. All animals that survived showed a less severe sternal phenotype, but were characterized by marked facial narrowing and paralysis resulting from a failure to form the somatic motor component of the VIIth (facial) nerve. Some Hoxb2 +/- and Hoxb2 -/- animals showed anterior transformations of the axis (C2) such that it more closely resembled the atlas (C1) or a change in the orientation of the anterior arch of the atlas compared with wildtype. Second branchial arch structures were unaffected in Hoxb2 -/- mice and expression of hindbrain markers appeared normal. Expression of Hoxb1 (142968) and Hoxb4 (142965), but not Hoxb3 (142966), were also altered in Hoxb2 -/- mice and appeared to contribute to the phenotype.
Barrow, J. R., Capecchi, M. R. Targeted disruption of the Hoxb-2 locus in mice interferes with expression of Hoxb-1 and Hoxb-4. Development 122: 3817-3828, 1996. [PubMed: 9012503] [Full Text: https://doi.org/10.1242/dev.122.12.3817]
Davenne, M., Maconochie, M. K., Neun, R., Pattyn, A., Chambon, P., Krumlauf, R., Rijli, F. M. Hoxa2 and Hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain. Neuron 22: 677-691, 1999. [PubMed: 10230789] [Full Text: https://doi.org/10.1016/s0896-6273(00)80728-x]
Pollock, R. A., Sreenath, T., Ngo, L., Bieberich, C. J. Gain of function mutations for paralogous Hox genes: implications for the evolution of Hox gene function. Proc. Nat. Acad. Sci. 92: 4492-4496, 1995. [PubMed: 7753831] [Full Text: https://doi.org/10.1073/pnas.92.10.4492]
Vieille-Grosjean, I., Huber, P. Transcription factor GATA-1 regulates human HOXB2 gene expression in erythroid cells. J. Biol. Chem. 270: 4544-4550, 1995. [PubMed: 7876223] [Full Text: https://doi.org/10.1074/jbc.270.9.4544]
Zhai, J., Lin, H., Canete-Soler, R., Schlaepfer, W. W. HoxB2 binds mutant SOD1 and is altered in transgenic model of ALS. Hum. Molec. Genet. 14: 2629-2640, 2005. [PubMed: 16079151] [Full Text: https://doi.org/10.1093/hmg/ddi297]