Abstract 1850: The role of Thoc1 in tissue homeostasis in the adult mouse

Abstract

Abstract Thoc1 encodes a protein (Thoc1) that interacts with the retinoblastoma protein (Rb). Thoc1 functions in an evolutionary conserved protein complex called THO that is involved in nuclear ribonucleoprotein particle (RNP) formation. Loss of THO function compromises the packaging of nascent RNA, which causes defects in transcription, RNA processing and mRNA export. In mice, Thoc1 is required for embryonic development. It is currently unknown whether Thoc1 is required in adult mice for normal tissue homeostasis. We hypothesize that different tissues will vary in their dependence on Thoc1, possibly based on their proliferative potential. To test this hypothesis, we conditionally deleted Thoc1 in adult mice in a wide variety of tissues using the Tamoxifen/CreER recombination system, and assessed the consequences on tissue homeostasis. Thoc1F/F:Rosa26CreER+/− (test) and Thoc1+/+:Rosa26CreER+/− (control) adult mice were treated with 2 mg/day Tamoxifen for 6 days. Slowly proliferating (liver, kidney, colon) and rapidly proliferating (small intestinal (S.I.)) tissue were collected 24 hours after the last treatment. Histological analysis shows Thoc1 loss disrupts the architecture of the small intestine (S.I.) but does not affect the other tissues examined. The functional unit of the S.I. is the crypt-villus axis. S.I. crypts contain rapidly proliferating stem and progenitor cells that continuously feed the differentiated, non-proliferative villus epithelium. The crypts proliferate so rapidly that the entire S.I. epithelium is replaced every three to five days. Interestingly, Thoc1 loss only causes apoptosis in the S.I. crypts, suggesting disruption of villi architecture following Thoc1 loss is a result of altered crypt function, not a direct effect of Thoc1 loss. Supporting this, the crypts of mice in which Thoc1 has been deleted also have a loss of cell proliferation. While the colon and S.I. have similar tissue architecture, the colon's rate of turnover is much slower. Therefore, it is not surprising the colon is not affected by Thoc1 loss. These findings support the hypothesis that tissues with a high cell proliferative potential require Thoc1. To explore this further, we examined how Thoc1 deletion would affect the highly proliferative hematopoietic system using the same test and control mice as previously listed. Further supporting the hypothesis, Thoc1 loss decreases the number of lymphocytes in the blood, but does not affect spleen and thymus (slowly proliferating tissues) histology. The results of this study suggest highly proliferative tissues that turnover rapidly require Thoc1, most likely to support the gene expression and cell growth necessary for rapid cell division. This hypothesis is significant as it predicts cancer cells will be more sensitive to Thoc1 loss than normal cells, a prediction verified by preliminary results in our lab. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1850. doi:1538-7445.AM2012-1850