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Since this small apoptotic response is unlikely to account fully for the dramatic size deficit observed in Atrxnull embryos, a possible proliferation defect was also investigated by immunohistochemical staining of 7.5 dpc embryo sections for the mitosis marker phosphorylated (Ser10) histone H3 [13]. Relative to the very high mitotic index observed in wild-type embryos, the proportion of mitotic cells observed in Atrxnull embryos at 7.5 dpc was dramatically reduced (Figure 6B). Taken together, these results suggest that the size deficit observed in Atrxnull embryos prior to lethality largely reflects a proliferative defect, with a minor but indirect contribution from increased apoptosis. Although a growth defect was also observed in Atrxnull ES cells (Figure 3A), in contrast to the Atrxnull embryos, the mitotic index of the ES cell population (as measured with the same antibody) was not depleted (Figure S1B). 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