Dear T N, Colledge W H, Carlton M B, Lavenir I, Larson T, Smith A J, Warren A J, Evans M J, Sofroniew M V, Rabbitts T H
MRC Laboratory of Molecular Biology, Cambridge, UK.
Development. 1995 Sep;121(9):2909-15. doi: 10.1242/dev.121.9.2909.
The HOX11 homeobox gene was identified via the translocation t(10;14) in T cell leukaemia. To determine the function of this gene in mice, null mutations were made using homologous recombination in ES cells to incorporate lacZ into the hox11 transcription unit. Production of beta-galactosidase from the recombinant hox11 allele in +/- mutants allowed identification of sites of hox11 expression which included the developing spleen. Newborn hox11 -/- mice exhibit asplenia. Spleen formation commences normally at E11.5 in hox11 -/- mutant embryos but the spleen anlage undergoes rapid and complete resorption between E12.5 and E13.5. Dying spleen cells exhibit molecular features of apoptosis, suggesting that programmed cell death is initiated at this stage of organ development in the absence of hox11 protein. Thus hox11 is not required to initiate spleen development but is essential for the survival of splenic precursors during organogenesis. This function for hox11 suggests that enhanced cell survival may result from the t(10;14) which activates HOX11 in T cell leukaemias, further strengthening the association between oncogene-induced cell survival and tumorigenesis.
HOX11 同源框基因是通过 T 细胞白血病中的 t(10;14)易位而被鉴定出来的。为了确定该基因在小鼠中的功能，利用胚胎干细胞中的同源重组将 lacZ 整合到 hox11 转录单位中，制造了无效突变。在 +/- 突变体中，重组 hox11 等位基因产生的β-半乳糖苷酶使得能够鉴定出 hox11 的表达位点，其中包括发育中的脾脏。新生的 hox11 -/- 小鼠表现为无脾。hox11 -/- 突变胚胎中脾脏形成在 E11.5 时正常开始，但脾脏原基在 E12.5 至 E13.5 之间迅速且完全吸收。濒死的脾细胞表现出凋亡的分子特征，这表明在缺乏 hox11 蛋白的器官发育阶段，程序性细胞死亡在此阶段启动。因此，hox11 不是启动脾脏发育所必需的，但对于器官发生过程中脾前体细胞的存活至关重要。hox11 的这一功能表明，在 T 细胞白血病中激活 HOX11 的 t(10;14)可能导致细胞存活率提高，进一步加强了癌基因诱导的细胞存活与肿瘤发生之间的关联。
