HLX (gene) explained

Homeobox Protein HB24 is a protein that in humans is encoded by the HLX gene.^{[1] [2] [3]}

Role in development

Hlx belongs to the class of homeobox transcription factors, initially cloned from a B-lymphocyte cell line.^[4] Targeted knockout of the gene has demonstrated its vital role in liver and gut organogenesis.^[5] Its expression is first noticed in embryonic day 9.5 (E9.5) in the splanchnic mesoderm caudal to the level of the heart and foregut pocket, and in the branchial arches. Around E10- E12.5, the expression becomes more prominent in the mesenchyme of the visceral organs of the gut such as liver, intestines and gall bladder.^[6] Hlx is essential for liver and gut expansion, but not for onset of their development. Heterozygous knockouts of Hlx (Hlx ^+/−) are normal whereas homozygous knockouts (Hlx ^−/–) develop severe hypoplasia of the liver and gut along with anaemia. Hlx controls the epithelial-mesenchymal interaction necessary for liver and gut expansion. At E8.0, the primary liver bud is formed from the midgut endoderm in response to signals from the cardiogenic mesoderm. This is followed by signals from the septum transversum that induce epithelial-mesenchymal transition in the hepatic progenitors of the gut endoderm.^{[7] [8]} In a third stage, these signaling factors induce the liver endoderm to undergo proliferation and form liver cords. The same factor controls gut proliferation, and Hlx governs its expression. Although these mice develop anaemia, it is likely due to insufficient support from the liver in producing matrix component needed for hematopoiesis rather than an intrinsic defect in the hematopoietic cells.

Further reading

• Najfeld V, Menninger J, Ballard SG, Deguchi Y, Ward DC, Kehrl JH . Two diverged human homeobox genes involved in the differentiation of human hematopoietic progenitors map to chromosome 1, bands q41-42.1 . Genes, Chromosomes & Cancer . 5 . 4 . 343–7 . November 1992 . 1283323 . 10.1002/gcc.2870050410 . 2106935 .
• Deguchi Y, Thevenin C, Kehrl JH . Stable expression of HB24, a diverged human homeobox gene, in T lymphocytes induces genes involved in T cell activation and growth . The Journal of Biological Chemistry . 267 . 12 . 8222–9 . April 1992 . 10.1016/S0021-9258(18)42430-1 . 1349016 . free .
• Deguchi Y, Kirschenbaum A, Kehrl JH . A diverged homeobox gene is involved in the proliferation and lineage commitment of human hematopoietic progenitors and highly expressed in acute myelogenous leukemia . Blood . 79 . 11 . 2841–8 . June 1992 . 1375114 . 10.1182/blood.V79.11.2841.2841. free .
• Allen JD, Lints T, Jenkins NA, Copeland NG, Strasser A, Harvey RP, Adams JM . Novel murine homeo box gene on chromosome 1 expressed in specific hematopoietic lineages and during embryogenesis . Genes & Development . 5 . 4 . 509–20 . April 1991 . 1672660 . 10.1101/gad.5.4.509 . free .
• Deguchi Y, Kehrl JH . Selective expression of two homeobox genes in CD34-positive cells from human bone marrow . Blood . 78 . 2 . 323–8 . July 1991 . 1712647 . 10.1182/blood.V78.2.323.323. free .
• Deguchi Y, Yamanaka Y, Theodossiou C, Najfeld V, Kehrl JH . High expression of two diverged homeobox genes, HB24 and HB9, in acute leukemias: molecular markers of hematopoietic cell immaturity . Leukemia . 7 . 3 . 446–51 . March 1993 . 7680402 .
• Deguchi Y, Agus D, Kehrl JH . A human homeobox gene, HB24, inhibits development of CD4+ T cells and impairs thymic involution in transgenic mice . The Journal of Biological Chemistry . 268 . 5 . 3646–53 . February 1993 . 10.1016/S0021-9258(18)53742-X . 8094082 . free .
• Nishimura DY, Purchio AF, Murray JC . Linkage localization of TGFB2 and the human homeobox gene HLX1 to chromosome 1q . Genomics . 15 . 2 . 357–64 . February 1993 . 8095486 . 10.1006/geno.1993.1068 .
• Quinn LM, Johnson BV, Nicholl J, Sutherland GR, Kalionis B . Grant Robert Sutherland . Isolation and identification of homeobox genes from the human placenta including a novel member of the Distal-less family, DLX4 . Gene . 187 . 1 . 55–61 . March 1997 . 9073066 . 10.1016/S0378-1119(96)00706-8 .
• Quinn LM, Kilpatrick LM, Latham SE, Kalionis B . Homeobox genes DLX4 and HB24 are expressed in regions of epithelial-mesenchymal cell interaction in the adult human endometrium . Molecular Human Reproduction . 4 . 5 . 497–501 . May 1998 . 9665637 . 10.1093/molehr/4.5.497 . free .
• Murthi P, Doherty V, Said J, Donath S, Brennecke SP, Kalionis B . Homeobox gene HLX1 expression is decreased in idiopathic human fetal growth restriction . The American Journal of Pathology . 168 . 2 . 511–8 . February 2006 . 16436665 . 1606485 . 10.2353/ajpath.2006.050637 .
• Becknell B, Hughes TL, Freud AG, Blaser BW, Yu J, Trotta R, Mao HC, Caligiuri de Jesús ML, Alghothani M, Benson DM, Lehman A, Jarjoura D, Perrotti D, Bates MD, Caligiuri MA . Hlx homeobox transcription factor negatively regulates interferon-gamma production in monokine-activated natural killer cells . Blood . 109 . 6 . 2481–7 . March 2007 . 17110450 . 1852195 . 10.1182/blood-2006-10-050096 .

Notes and References

1. Deguchi Y, Moroney JF, Wilson GL, Fox CH, Winter HS, Kehrl JH . Cloning of a human homeobox gene that resembles a diverged Drosophila homeobox gene and is expressed in activated lymphocytes . The New Biologist . 3 . 4 . 353–63 . April 1991 . 1676597 .
2. Kennedy MA, Rayner JC, Morris CM . Genomic structure, promoter sequence, and revised translation of human homeobox gene HLX1 . Genomics . 22 . 2 . 348–55 . July 1994 . 7806220 . 10.1006/geno.1994.1394 .
3. Web site: Entrez Gene: HLX1 H2.0-like homeobox 1 (Drosophila).
4. Allen JD, Lints T, Jenkins NA, Copeland NG, Strasser A, Harvey RP, Adams JM . Novel murine homeo box gene on chromosome 1 expressed in specific hematopoietic lineages and during embryogenesis . Genes & Development . 5 . 4 . 509–20 . 1991 . 1672660 . 10.1101/gad.5.4.509. free .
5. Hentsch B, Lyons I, Li R, Hartley L, Lints TJ, Adams JM, Harvey RP . Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut . Genes & Development . 10 . 1 . 70–9 . 1996 . 8557196 . 10.1101/gad.10.1.70. free .
6. Lints TJ, Hartley L, Parsons LM, Harvey RP . Mesoderm-specific expression of the divergent homeobox gene Hlx during murine embryogenesis . Developmental Dynamics . 205 . 4 . 457–70 . 1996 . 8901056 . 10.1002/(SICI)1097-0177(199604)205:4<457::AID-AJA9>3.0.CO;2-H . 33762532 . free .
7. Douarin NM . An experimental analysis of liver development . Medical Biology . 53 . 6 . 427–55 . 1975 . 765644 .
8. Fukuda-Taira S . Hepatic induction in the avian embryo: specificity of reactive endoderm and inductive mesoderm . Journal of Embryology and Experimental Morphology . 63 . 111–25 . 1981 . 7310284 .