Response to Heard et al.
نویسندگان
چکیده
H eard et al (2015) generated cIap1 / Xiap / mice and were surprised to find them to be viable and fertile, because we had reported (Moulin et al, 2012) that cIap1 / Xiap / mice died by day E12.5 of embryogenesis (Moulin et al, 2012 Figs 1B and 2B and Supplementary Fig S1A). We are working with Heard et al (2015) in an attempt to determine why. It is, however, clear that failure of our cIap2cIap1 / Xiap / mice to survive past E12.5 is not due to non-functional cIap2 / genes. Three types of cross indicate that the cIap2 locus, which is carried by our cIap1 / mice, does produce functional cIAP2. Firstly, comparison of the phenotypes of the cIap2cIap1 / mice, which are viable and fertile, with the cIap2 / cIap1 / mice, which die at E12.5, indicates that the cIap2 locus can function, at least to the extent needed to allow normal development when Xiap is present (Moulin et al, 2012). Secondly, when specific deletion of cIap1 in B cells was combined with whole body cIap2 deletion, it led to more profound B-cell expansion than deletion of either IAP alone (Gardam et al, 2011). Thirdly, deletion of cIap1 in myeloid cells on either a cIap2 / or cIap2 / Xiap / background triggered splenomegaly, increased neutrophils and monocytes, inflammatory cytokine production and spontaneous inflammatory arthritis, whereas deletion of Xiap, cIap1 or cIap2 alone did not (Wong et al, 2014; Lawlor et al, 2015). In addition to the differences in viability of the cIap1 / Xiap / mice, Heard et al (2015) found much higher levels of cIAP2 protein in their cIap1 / mouse embryonic fibroblasts (MEFs) than we reported in our cIap1 / MEFs. Furthermore, Heard et al (2015) confirmed this difference: when they directly compared our cIap1 / MEFs with their cIap1 / MEFs, they saw that ours had very low to undetectable levels of cIAP2 protein (like wild-type MEFs), whereas theirs had much higher levels of cIAP2 (Fig 1F, compare lanes 1, 2 and 4). Consistent with their finding that levels of cIAP2 rise in the absence of cIAP1 in MEFs, they also found elevated levels of cIAP2 protein in several tissues of cIap1 / Xiap / mice. Although we did not observe elevated cIAP2 in our cIap2cIap1 / MEFs, their finding of increased cIAP2 in their cIap1 / MEFs is consistent with data from several laboratories (including our own) showing that absence or depletion of cIAP1 leads to activation of non-canonical NF-jB and cIAP2 up-regulation (Varfolomeev et al, 2007; Vince et al, 2007; Darding et al, 2011). Indeed, as Heard et al (2015) show, our cIap2 cIap1 / MEFs have elevated cIap2 mRNA expression when compared with their cIap1 cIap2 cIAP1-proficient counterparts. This indicates a potential defect in translation or stability of the cIAP2 protein in our MEFs. Note, however, that in our hands, immortalised MEFs are highly genetically variable, with a tendency to lose the expression of proteins, often seemingly at random (Cook et al, 2014). Thus, it remains possible that the particular line of immortalised MEFs that we shared with Heard et al (2015) are not truly representative of the situation elsewhere in the mice. Why might MEFs derived from our cIap2cIap1 / and cIap2cIap1 / Xiap / mice have much lower levels of cIAP2 than the MEFs from their cIap1 / and cIap1 / Xiap / mice? If the differences in cIAP2 levels in the MEFs are reflected in vivo, one reason their cIap1 / Xiap / mice are viable, whereas our cIap1 / Xiap / mice die in mid-embryogenesis, might be differing levels of cIAP2 present during embryogenesis. In a number of molecular pathways minimum threshold levels of protein are required for normal development. As we have only observed one morphological anomaly, namely defects in the integrity of the atrial walls of the heart (Moulin et al, 2012), it is possible that in one experimental system there is enough IAP2 protein to avoid this lethal defect, whereas in another there is not. Furthermore, if this is the case, is the amount of cIAP2 aberrantly low in our mice, or is it aberrantly high in theirs, or both? If there are differences in the production of cIAP2 protein, it might be due to the way the closely linked cIap1 locus was deleted in each of the strains. Heard et al (2015) used cIap1 / mice as described in Conze et al (2005). These were generated from 129/Sv E14 embryonic stem (ES) cells by homologous recombination of a neomycin (Neo) resistance gene in reverse orientation in place of the transcription initiation start codon and the first BIR domain of cIap1 (see Fig 1A of Conze et al, 2005). These mice were backcrossed to C57BL/6 mice for multiple generations. We generated cIap2cIap1 mice by sequentially targeting the same chromosome in BRUCE embryonic stem cells, which were derived from C57BL/6 mice (Koentgen et al,
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ورودعنوان ژورنال:
- The EMBO journal
دوره 34 19 شماره
صفحات -
تاریخ انتشار 2015