Disease relevance of Hoxb4

• Enforced expression of Hoxb4 dramatically increases the regeneration of murine hematopoietic stem cells (HSCs) after transplantation and enhances the repopulation ability of human severe combined immunodeficiency (SCID) repopulating cells [1].
• Hox-2.6 is expressed in fetal and adult tissues and is modulated during the differentiation of F9 teratocarcinoma stem cells [2].

High impact information on Hoxb4

• Hoxb-4 (Hox-2.6) mutant mice show homeotic transformation of a cervical vertebra and defects in the closure of the sternal rudiments [3].
• Introduction of a subtle mutation into the Hox-2.6 locus in embryonic stem cells [4].
• We have developed this procedure at the hypoxanthine phosphoribosyltransferase (hprt) locus and subsequently isolated ES cells with a premature stop codon in the homeobox of Hox-2.6 (ref. 14) [4].
• In contrast, ectopic Hoxb2 and Hoxb4 are unable to induce expression, indicating that in vivo this enhancer preferentially responds to labial family members [5].
• Multiple spatially specific enhancers are required to reconstruct the pattern of Hox-2.6 gene expression [6].

Biological context of Hoxb4

• Separate RA- and Hox-responsive enhancers mediate the two phases of Rarb expression: a regulatory mechanism remarkably similar to that of Hoxb4 [7].
• Here we find that mice deficient in both Hoxb3 and Hoxb4 have defects in endogenous hematopoiesis with reduced cellularity in hematopoietic organs and diminished number of hematopoietic progenitors without perturbing lineage commitment [8].
• Furthermore, treatment with cytostatic drugs demonstrated slower cell cycle kinetics of hematopoietic stem cells deficient in Hoxb3 and Hoxb4, resulting in increased tolerance to antimitotic drugs [8].
• Multiple positive and negative regulatory elements in the promoter of the mouse homeobox gene Hoxb-4 [9].
• The complex architecture of the Hoxb-4 promoter provides the framework for fine-tuned transcriptional regulation during embryonic development [9].

Anatomical context of Hoxb4

• Thrombopoietin stimulates Hoxb4 expression: an explanation for the favorable effects of TPO on hematopoietic stem cells [10].
• Hoxd4 and Hoxb4 expression in the embryonic hindbrain is anteriorized by retinoic acid (RA) treatment of mid-gestation mouse embryos [11].
• Collectively, these data suggest a direct physiological role of Hoxb4 and Hoxb3 in regulating stem cell regeneration and that these genes are required for maximal proliferative response [8].
• Initiation of rhombomeric Hoxb4 expression requires induction by somites and a retinoid pathway [12].
• A novel mouse model lacking the entire Hoxb4 gene exhibits significantly reduced cellularity in spleen and bone marrow (BM) and a subtle reduction in red blood cell counts and hemoglobin values [1].

Associations of Hoxb4 with chemical compounds

• Characterization of a prerhombomeric enhancer from Hoxb4 reveals that a retinoic acid (RA) response element is an essential component of the early neural response to somite (s) signaling and can interpret positional information for setting the anterior boundary of expression [12].

Physical interactions of Hoxb4

• As these two factors are able to mediate opposing transcriptional effects by reorganizing the local chromatin environment, the relative levels of NFY and YY1 binding could represent a mechanism for balancing activation and repression of Hoxb4 through the same site [13].

Regulatory relationships of Hoxb4

• RESULTS: The Hoxb4 gene was highly expressed in HSCs derived from mel-18(-/-) mice [14].

Other interactions of Hoxb4

• Rostral expression boundaries of Hoxb-3 and Hoxb-4 are displaced from their normal positions at r4/5 and r6/7 to the approximate positions of r3/4 and r4/5, respectively [15].
• However, no obvious alterations in the spatial pattern of expression of Hoxb-1, Hoxb-4 and Hoxb-5 were observed in day 9.5 p.c. embryos [16].
• In contrast, both the Hoxb4(PolII) and the previously described Hoxb2(PolII) alleles that have body wall defects have been shown to disrupt the expression of both Hoxb2 and Hoxb4 in cell types that contribute to body wall formation [17].
• To explore the molecular basis of this effect, we postulated that Hoxb4 might mediate at least part of the TPO effect on these cells [10].
• We also demonstrated that upstream stimulating factor 1 (USF-1), a transcription factor previously shown to regulate Hoxb4 expression, is also induced by TPO in a p38-dependent manner [10].

Analytical, diagnostic and therapeutic context of Hoxb4

• Three different alleles of the Hoxb4 locus were generated by gene targeting in mice [17].
• The expression levels of mel-18 and Hoxb4 were measured by quantitative real-time reverse transcription polymerase chain reaction [14].
• Whole-mount in situ hybridization using digoxygenin-labeled RNA probes was used to monitor the regions of expression of Hoxb-4, Pax-3 and Emx-2 [18].

References