Conditional abrogation of Ddx3x reveals its essential role in lymphocyte development and partial compensation by Y chromosome

Abstract

Abstract Ddx3x on the X-chromosome encodes a DEAD-box RNA helicase with putative roles in RNA metabolism, cell cycle progression, apoptosis, and viral immunity. We previously found that hematopoietic-specific hemizygosity of Ddx3x studies caused a marked reduction in the frequencies of natural killer (NK) and B cells in peripheral lymphoid organs of male mice (Liu et al. bioRxiv 2018). No homozygous Ddx3x-deficient female pups were ever obtained, suggesting that hematopoietic loss of this gene contributes to the embryonic lethality observed in germline Ddx3x knockout mice. To assess cell-lineage intrinsic roles for Ddx3x in B-cell and NK-cell development, we bred Ddx3x-floxed mice with Mb1-Cre and Ncr1-iCre mice, respectively. While hemizygous male Ddx3x-deficient mice display mild reductions in B-cell (Mb1-Cre) and NK-cell (Ncr1-iCre) frequencies, homozygous Ddx3x-deficient female mice from each were almost completely devoid of the relevant cell lineages. B-cell loss was evident from the pro-B cells stage, with B cells surviving beyond this stage showing evidence of having escaped deletion of Ddx3x. Ncr1-iCre-mediated deletion of Ddx3x completely abrogated development of both NK cells and other Ncr1-expressing innate lymphoid cells. Thus, DDX3 plays an essential role in the lymphocyte development, where Ddx3y may partially compensate for loss of Ddx3x in these lineages.