THOC5, a member of the mRNA export complex, contributes to processing of a
subset of wingless/integrated (Wnt) target mRNAs and integrity of the gut
epithelial barrier
THO (Suppressors of the transcriptional defects of hpr1 delta by
overexpression) complex 5 (THOC5), an mRNA export protein, is involved in the
expression of only 1% of all genes. Using an interferon inducible knockout
mouse system, we have previously shown that THOC5 is an essential element in
the maintenance of hematopoietic stem cells and cytokine-mediated
hematopoiesis in adult mice. Here we interrogate THOC5 function in cell
differentiation beyond the hematopoietic system and study pathological changes
caused by THOC5 deficiency. To examine whether THOC5 plays a role in general
differentiation processes, we generated tamoxifen inducible THOC5 knockout
mice. We show here that the depletion of THOC5 impaired not only hematopoietic
differentiation, but also differentiation and self renewal of the gut
epithelium. Depletion of the THOC5 gene did not cause pathological alterations
in liver or kidney.We further show that THOC5 is indispensable for processing
of mRNAs induced by Wnt (wingless/integrated) signaling which play key roles
in epithelial cell differentiation/proliferation. A subset of Wnt target
mRNAs, SRY-box containing gene 9 (Sox9), and achaete-scute complex homolog 2
(Ascl2), but not Fibronectin 1 (Fn1), were down-regulated in THOC5 knockout
intestinal cells. The down-regulated Wnt target mRNAs were able to bind to
THOC5. Furthermore, pathological alterations in the gastrointestinal tract
induced translocation of intestinal bacteria and caused sepsis in mice. The
bacteria translocation may cause Toll-like receptor activation. We identified
one of the Toll-like receptor inducible genes, prostaglandin-endoperoxidase
synthase 2 (Ptgs2 or COX2) transcript as THOC5 target mRNA. THOC5 is
indispensable for processing of only a subset of mRNAs, but plays a key role
in processing of mRNAs inducible by Wnt signals. Furthermore, THOC5 is
dispensable for general mRNA export in terminally differentiated organs,
indicating that multiple mRNA export pathways exist. These data imply that
THOC5 may be a useful tool for studying intestinal stem cells, for modifying
the differentiation processes and for cancer therapy