Alternative titles; symbols
HGNC Approved Gene Symbol: HOXB8
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:48,612,346-48,615,292 (from NCBI)
Using RT-PCR and in situ hybridization, Greer and Capecchi (2002) detected Hoxb8 expression in regions of the adult mouse central nervous system including the cervical spinal cord, brainstem, forebrain, olfactory bulb, basal ganglia, hippocampus, cortex, and cerebellum.
Yekta et al. (2004) found that miR196 (608632) has extensive evolutionarily conserved complementarity to messages of HOXB8, HOXC8 (142970), and HOXD8 (142985). RNA fragments diagnostic of miR196-directed cleavage of HOXB8 were detected in mouse embryos. Cell culture experiments demonstrated downregulation of HOXB8, HOXC8, HOXD8, and HOXA7 (142950) and supported the cleavage mechanism for miR196-directed repression of HOXB8.
As reviewed by Acampora et al. (1989), the homeobox region-2 contains 9 homeobox genes in 180 kb of DNA on chromosome 17. The HOXB8 gene is flanked by the HOXB9 gene (142964) on its 5-prime side and the HOXB7 gene (142962) on its 3-prime side.
Using gene targeting, Greer and Capecchi (2002) generated mice with disruptions of Hoxb8. In the mutant mice they observed excessive pathologic grooming behavior, leading to hair removal and self-inflicted wounds at overgroomed sites. Using histologic and behavioral analysis, they detected no skin or peripheral nervous system abnormalities in Hoxb8 mutants and concluded that the abnormal grooming behavior is a result of CNS abnormalities.
Greer and Capecchi (2002) noted that the behavior of Hoxb8 knockout mice is not unlike that of humans suffering from the obsessive-compulsive spectrum disorder (OCD) trichotillomania (613229). Consistent with this, they detected expression of Hoxb8 in regions of the CNS known as the 'OCD-circuit,' where OCD patients are thought to have abnormal metabolic activity. They hypothesized that trichotillomania may arise from a misregulation of an innate autogrooming behavior and presented the Hoxb8 mutant mice as a model of OCD-like phenotypes.
The grooming phenotype in Hoxb8 knockout mice reported by Greer and Capecchi (2002) differs significantly from the axial skeletal defects and abnormal forearm clasping reflex reported for Hoxb8 mutant mice generated by van den Akker et al. (1999). Greer and Capecchi (2002) argued that the skeletal and forelimb defects observed by van den Akker et al. (1999) were due to the presence of the bacterial lacZ gene in the mutant mice. Greer and Capecchi (2002) similarly concluded that skeletal defects observed in one of their Hoxb8 mutant lines were due to the presence of a bacterial neo(r) gene in the Hoxb8 locus interfering with the expression of neighboring Hox genes.
The transcription factor Hoxb8 seems to mediate the induction of Sonic hedgehog (Shh; 600725) by retinoic acid (RA) in the forelimb in that Hoxb8 is upregulated as an immediate-early response to ectopic RA administered to the chick forelimb bud. Ectopic RA does not lead to Hoxb8 induction in the hindlimb bud, however, owing to the presence of an unknown hindlimb-specific inhibitory activity. Hypothesizing that the unknown hindlimb inhibitory activity might be mediated by a small silencing RNA, Hornstein et al. (2005) used a conditional knockout allele of Dicer (606241), a key enzyme required for producing functional miRNAs from their precursors, to test whether the inhibition of Hoxb8 induction by RA in hindlimb is relieved by the removal of Dicer activity. In Dicer mutant animal hindlimbs, RA induced the expression of Hoxb8. Loss of Dicer activity does not affect expression of other known patterning genes in the developing limb bud. Thus, the previously uncharacterized inhibitory activity is lost in the absence of Dicer. Hornstein et al. (2005) showed that miR196 (608632) acts upstream of Hoxb8 and Shh in vivo in the context of limb development, thereby identifying a previously observed but uncharacterized inhibitory activity that operates specifically in the hindlimb. Hornstein et al. (2005) concluded that miR196 functions in a fail-safe mechanism to assure the fidelity of expression domains that are primarily regulated at the transcriptional level, supporting the idea that many vertebrate miRNAs may function as a secondary level of gene regulation.
Holstege et al. (2008) found that, in addition to pathologic grooming, Hoxb8-null mice showed impaired thermal and nociceptive responses. The number of neurons in the superficial layers of the dorsal horn was lower in mutants than in controls at birth and in adults, resulting in a mediolaterally narrowed dorsal horn in the lumbar region. This change led to a narrowed primary afferent projection area, although cell counts and neurochemistry of the dorsal root ganglia were normal. BrdU labeling experiments and gene expression studies showed that loss of Hoxb8 impaired development of organized laminae I and II of dorsal neurons at specific axial levels at about embryonic day 15.5.
Chen et al. (2010) demonstrated that in mouse brain, Hoxb8-labeled cells are derived exclusively from microglia that are most likely formed in the bone marrow. Hoxb8-mutant mice had decreased numbers of microglia in the brain compared to wildtype. Transplantation of wildtype bone marrow into Hoxb8-mutant mice rescued the phenotype of pathologic grooming. Conditional restriction of the Hoxb8 deletion to the hematopoietic system resulted in excessive grooming and hair removal behavior defects, without inducing spinal cord defects in nociception. The findings indicated that the defect in these mice is not related to nociceptive or sensory defect, as had been suggested by Holstege et al. (2008). Conditional Hoxb8 deletion restricted to the spinal cord generated mice with the spinal cord sensory defect but normal grooming behavior. Chen et al. (2010) concluded that the pathologic grooming behavior results from a deficiency of microglia in the brain, illustrating the importance of microglia for normal brain function.
Acampora, D., D'Esposito, M., Faiella, A., Pannese, M., Migliaccio, E., Morelli, F., Stornaiuolo, A., Nigro, V., Simeone, A., Boncinelli, E. The human HOX gene family. Nucleic Acids Res. 17: 10385-10402, 1989. [PubMed: 2574852] [Full Text: https://doi.org/10.1093/nar/17.24.10385]
Chen, S.-K., Tvrdik, P., Peden, E., Cho, S., Wu, S., Spangrude, G., Capecchi, M. R. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141: 775-785, 2010. [PubMed: 20510925] [Full Text: https://doi.org/10.1016/j.cell.2010.03.055]
Greer, J. M., Capecchi, M. R. Hoxb8 is required for normal grooming behavior in mice. Neuron 33: 23-34, 2002. [PubMed: 11779477] [Full Text: https://doi.org/10.1016/s0896-6273(01)00564-5]
Holstege, J. C., de Graaff, W., Hossaini, M., Cano, S. C., Jaarsma, D., van den Akker, E., Deschamps, J. Loss of Hoxb8 alters spinal dorsal laminae and sensory responses in mice. Proc. Nat. Acad. Sci. 105: 6338-6343, 2008. [PubMed: 18430798] [Full Text: https://doi.org/10.1073/pnas.0802176105]
Hornstein, E., Mansfield, J. H., Yekta, S., Hu, J. K.-H., Harfe, B. D., McManus, M. T., Baskerville, S., Bartel, D. P., Tabin, C. J. The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature 438: 671-674, 2005. [PubMed: 16319892] [Full Text: https://doi.org/10.1038/nature04138]
van den Akker, E., Reijnen, M., Korving, J., Brouwer, A., Meijlink, F., Deschamps, J. Targeted inactivation of Hoxb8 affects survival of a spinal ganglion and causes aberrant limb reflexes. Mech. Dev. 89: 103-114, 1999. [PubMed: 10559485] [Full Text: https://doi.org/10.1016/s0925-4773(99)00212-9]
Yekta, S., Shih, I., Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304: 594-596, 2004. [PubMed: 15105502] [Full Text: https://doi.org/10.1126/science.1097434]