Disease relevance of Hoxa1

• Unexpectedly, in Hoxa1/Hoxa2 double mutants, the penetrance of cleft palate is dramatically reduced [1].
• We have previously identified a 10 bp element, called CE2, which is located approximately 3 kilobases 3' of the Hoxa1 coding region in the RAIDR5 enhancer, and which binds to an approximately 170 kd protein in retinoic acid treated P19 embryonal carcinoma cells [2].
• We previously identified a 3' enhancer called the RAIDR5, which contained a DR5 retinoic acid response element (RARE) and was responsible for the retinoic acid (RA)-associated expression of the murine Hoxa-1 gene in teratocarcinoma cells [3].
• Of all common integration sites, a small region of 19 kb in the Hoxa gene locus, mostly between Hoxa6 and Hoxa10, represented 18% of all integrations in the E2a-PBX1 B-cell leukemia and was targeted in 86% of these leukemias compared to 17% in control tumors [4].

High impact information on Hoxa1

• Hoxa1 is transiently expressed in the developing hindbrain; its targeted inactivation in mice results in severe abnormalities of the otic capsule and membranous labyrinth [5].
• Retinoic acid rescues inner ear defects in Hoxa1 deficient mice [5].
• Here we show that a single maternal administration of a low dose of the vitamin A metabolite retinoic acid is sufficient to compensate the requirement for Hoxa1 function [5].
• Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression [6].
• The Hox-1.6 gene disrupted in embryonic stem cells by homologous recombination was introduced into the mouse germline [6].

Biological context of Hoxa1

• The Hoxa1 mutant phenotype is consistent with a partial misspecification of the presumptive r4 territory that results from partial Hoxb1 activation [7].
• Differences in gene expression between wild type and Hoxa1 knockout embryonic stem cells after retinoic acid treatment or leukemia inhibitory factor (LIF) removal [8].
• Local alterations of Krox-20 and Hox gene expression in the hindbrain suggest lack of rhombomeres 4 and 5 in homozygote null Hoxa-1 (Hox-1.6) mutant embryos [9].
• Expression of another lacZ reporter gene that directs beta-galactosidase activity predominantly in rhombomere 2 is suppressed in the Hoxa-1 transgenic embryos [10].
• At gestation day 9.5, two domains of strong Hoxb-1 expression are found in the anterior region of the hindbrains of Hoxa-1 transgenic embryos [10].

Anatomical context of Hoxa1

• Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse [11].
• Two of these genes, Hoxa1 and Hoxa2, have been shown to be required for proper patterning of the early mouse hindbrain and the associated neural crest [11].
• We have generated Hoxa1(-/-) embryonic stem (ES) cells (named Hoxa1-15) from Hoxa1(-/-) mutant blastocysts to study the Hoxa1 signaling pathway [8].
• While no obvious change in the morphology of the trigeminal or facial-acoustic ganglia is evident, phenotypic changes do occur in neurons that emanate from rhombomeres 2 and 3 in the Hoxa-1 transgenic embryos [10].
• GFP expression in the foregut pocket of Hoxa1(GFPneo) embryos suggests a role for Hoxa1 in foregut-mediated differentiation of the cardiogenic mesoderm [12].

Associations of Hoxa1 with chemical compounds

• Interestingly, we also find that the Hoxa-1 expression response to RA treatment is not entirely controlled by the RARE, suggesting the existence of other retinoid-induced factors mediating the Hoxa-1 response to RA and/or the presence of additional RAREs [13].

Physical interactions of Hoxa1

• Orientation of the Hoxa complex and placement of the Hd locus distal to Hoxa2 on mouse chromosome 6 [14].

Regulatory relationships of Hoxa1

• Since Hoxa1 is expressed early and Hoxc13 is expressed late in mouse embryogenesis, this study shows that single-copy GFP gene fusions can be used through most of mouse embryogenesis [12].
• To examine the role of the Hox 1.6 gene, we have stably transfected F9 stem cells with a cDNA containing the complete coding sequence of Hox 1.6 under the control of the mouse metallothionein promoter [15].

Other interactions of Hoxa1

• Failure to express Hoxb1 to this boundary in Hoxa1 mutant embryos initiates a cascade of gene misexpressions that result in misspecification of the hindbrain compartments from r2 through r5 [11].
• Neuronal defects in the hindbrain of Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox genes [7].
• Here, we show that the fluorescent signals produced by single-copy, targeted GFP in-frame fusions with two different murine Hox genes, Hoxa1 and Hoxc13, are readily detectable by using confocal microscopy [12].
• In E8.0-8.5 Hoxa-1 mutants, cad6 expression was suppressed in the region of rhombomeres 4 to 6, although that in the other regions was not essentially affected [16].
• The set of defects associated with the disruption of Hox-1.6 is distinct from and nonoverlapping with that of the closely linked Hox-1.5 gene [17].

Analytical, diagnostic and therapeutic context of Hoxa1

• 6. Northern blot analysis demonstrates that Ghox-lab and Hox 1.6 transcripts are both present at high levels during early stages of chick and mouse development, with a subsequent decline in abundance to very low levels by the time limb mesenchyme begins to differentiate [18].
• In situ hybridization of Hox 1.6 probes to mouse embryos of day 7.5 or 8.0 indicate that the Hox 1.6 transcript has a temporal and spatial distribution very similar to that of Ghox-lab in the chick embryo [18].
• Molecular cloning and analysis of a group of genes differentially expressed in cells which overexpress the Hoxa-1 homeobox gene [19].
• Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation [20].

References