Alternative titles; symbols
HGNC Approved Gene Symbol: LHX8
Cytogenetic location: 1p31.1 Genomic coordinates (GRCh38) : 1:75,128,434-75,199,454 (from NCBI)
Members of the LIM homeobox gene family, such as LHX8, encode transcription regulators that share common structural features. They all contain 2 tandemly repeated cysteine-rich double-zinc finger motifs, called LIM domains, in addition to a homeodomain. The homeodomain is a DNA-binding domain, and the LIM domains are essential for regulating the activity of these molecules by interacting with other proteins. Members of the LIM homeobox gene family are required for the patterning or the specification and differentiation of different cell types during embryonic development (Zhao et al., 1999).
Mouse Lhx8 was identified by Matsumoto et al. (1996) and Grigoriou et al. (1998). During mouse embryogenesis, Lhx8 was expressed in several regions of the head, including the maxillary and mandibular processes and the ventral forebrain.
Using RT-PCR, Pangas et al. (2006) found that Lhx8 was preferentially expressed in adult mouse testis and ovary. In situ hybridization showed Lhx8 expression in oocytes of germ cell cysts and primordial, primary, and antral follicles.
Hartz (2013) mapped the LHX8 gene to chromosome 1p31.1 based on an alignment of the LHX8 sequence (GenBank AK094667) with the genomic sequence (GRCh37).
Kitanaka et al. (1998) mapped the mouse Lhx8 gene to chromosome 3, band H3-4. Homologs of genes in that region had been mapped to human chromosome 4q25-q31, a region linked to craniofacial clefting (Mitchell et al., 1995).
Zhao et al. (1999) examined expression of Lhx8 at different stages during palatogenesis and generated a mutant mouse with a targeted deletion of the gene. Lhx8 was continuously expressed in the mesenchyme of the normal developing palatal structures. Disruption of Lhx8 gene function caused impairment in palatal shelf contact and fusion, leading to formation of a cleft secondary palate. Zhao et al. (1999) suggested LHX8 as a candidate gene for the isolated nonsyndromic form of cleft palate in humans.
Zhao et al. (2003) reported that mice with a null mutation in the Lhx8 gene were deficient in development of forebrain cholinergic neurons. The Lhx8 mutants lacked the nucleus basalis, a major source of cholinergic input to the cerebral cortex. In addition, the number of cholinergic neurons was reduced in several other areas of the subcortical forebrain in these mutants. Although cholinergic neurons were not formed, initial steps in their specification appeared to be preserved, as indicated by a presence of cells expressing a truncated Lhx8 mRNA and mRNA of the homeobox gene Gbx1 (603354). These results provided genetic evidence supporting an important role for Lhx8 in development of cholinergic neurons in the forebrain.
Using microarray analysis and in situ hybridization, Pangas et al. (2006) showed that Lhx8 expression was drastically downregulated in Sohlh1 (610224) -/- mouse ovaries. Lhx8 -/- ovaries lacked germ cells and appeared histologically identical to adult Sohlh1 -/- ovaries. Pangas et al. (2006) proposed that LHX8 is downstream of SOHLH1 and that part of the Sohlh1 -/- phenotype is secondary to disruption of Lhx8 expression.
Flandin et al. (2011) found that double knockout of Lhx6 (608215) and Lhx8 in mice resulted in interneuron defects in several brain regions, with failure to express Shh (600725) in early-born neurons in the medial ganglionic eminence (MGE). Both Lhx6 and Lhx8 bound an Shh enhancer and activated Shh expression in the MGE mantle zone, which in turn promoted development of the rostrodorsal MGE.
Flandin, P., Zhao, Y., Vogt, D., Jeong, J., Long, J., Potter, G., Westphal, H., Rubenstein, J. L. R. Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. Neuron 70: 939-950, 2011. [PubMed: 21658586] [Full Text: https://doi.org/10.1016/j.neuron.2011.04.020]
Grigoriou, M., Tucker, A. S., Sharpe, P. T., Pachnis, V. Expression and regulation of Lhx6 and Lhx7, a novel subfamily of LIM homeodomain encoding genes, suggests a role in mammalian head development. Development 125: 2063-2074, 1998. [PubMed: 9570771] [Full Text: https://doi.org/10.1242/dev.125.11.2063]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/31/2013.
Kitanaka, J., Takemura, M., Matsumoto, K., Mori, T., Wanaka, A. Structure and chromosomal localization of a murine LIM/homeobox gene, Lhx8. Genomics 49: 307-309, 1998. [PubMed: 9598319] [Full Text: https://doi.org/10.1006/geno.1998.5203]
Matsumoto, K., Tanaka, T., Furuyama, T., Kashihara, Y., Mori, T., Ishii, N., Kitanaka, J., Takemura, M., Tohyama, M., Wanaka, A. L3, a novel murine LIM-homeodomain transcription factor expressed in the ventral telencephalon and the mesenchyme surrounding the oral cavity. Neurosci. Lett. 204: 113-116, 1996. [PubMed: 8929991] [Full Text: https://doi.org/10.1016/0304-3940(96)12341-7]
Mitchell, L. E., Healey, S. C., Chenevix-Trench, G. Evidence for an association between nonsyndromic cleft lip with or without cleft palate and a gene located on the long arm of chromosome 4. Am. J. Hum. Genet. 57: 1130-1136, 1995. [PubMed: 7485164]
Pangas, S. A., Choi, Y., Ballow, D. J., Zhao, Y., Westphal, H., Matzuk, M. M., Rajkovic, A. Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proc. Nat. Acad. Sci. 103: 8090-8095, 2006. [PubMed: 16690745] [Full Text: https://doi.org/10.1073/pnas.0601083103]
Zhao, Y., Guo, Y.-J., Tomac, A. C., Taylor, N. R., Grinberg, A., Lee, E. J., Huang, S., Westphal, H. Isolated cleft palate in mice with a targeted mutation of the LIM homeobox gene Lhx8. Proc. Nat. Acad. Sci. 96: 15002-15006, 1999. [PubMed: 10611327] [Full Text: https://doi.org/10.1073/pnas.96.26.15002]
Zhao, Y., Marin, O., Hermesz, E., Powell, A., Flames, N., Palkovits, M., Rubenstein, J. L. R., Westphal, H. The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain. Proc. Nat. Acad. Sci. 100: 9005-9010, 2003. [PubMed: 12855770] [Full Text: https://doi.org/10.1073/pnas.1537759100]