Multiple Hemopoietic Defects and Lymphoid Hyperplasia in Mice Lacking the Transcriptional Activation Domain of the c-Rel Protein

Abstract

The c-rel protooncogene encodes a member of the Rel/nuclear factor (NF)-κB family of transcriptional factors. To assess the role of the transcriptional activation domain of c-Rel in vivo, we generated mice expressing a truncated c-Rel (Δc-Rel) that lacks the COOH-terminal region, but retains a functional Rel homology domain. Mice with an homozygous mutation in the c-rel region encoding the COOH terminus of c-Rel (c-relΔCT/ΔCT) display marked defects in proliferative and immune functions. c-relΔCT/ΔCT animals present histopathological alterations of hemopoietic tissues, such as an enlarged spleen due to lymphoid hyperplasia, extramedullary hematopoiesis, and bone marrow hypoplasia. In older c-relΔCT/ΔCT mice, lymphoid hyperplasia was also detected in lymph nodes, liver, lung, and stomach. These animals present a more severe phenotype than mice lacking the entire c-Rel protein. Thus, in c-relΔCT/ΔCT mice, the lack of c-Rel activity is less efficiently compensated by other NF-κB proteins.

A single NFκB system for both canonical and non-canonical signaling

“…Further, dendritic cells lacking cRel:p50 are defective in CD40L-induced cell survival [20] and displayed reduced maturation phenotype [21]. However, the results from domain mutation studies are not fully explained: removal of the C-terminal activation domain of cRel results in enlarged lymph nodes and lymphoid hyperplasia [22].…”

NF-κB and the immune response

“…Following adoptive transfer, B cells from rela À/À mice exhibit markedly diminished class switching, despite a modest loss of lymphocyte proliferation following various stimuli (Doi et al, 1997). Likewise, c-Rel-deficient mice, or mice lacking the c-Rel C-terminal transactivation domain, fail to generate a productive humoral immune response suggesting a requirement for c-Rel in class switch recombination (Ko¨ntgen et al, 1995;Zelazowski et al, 1997;Carrasco et al, 1998). B cells from nfkb1 À/À mice exhibit decreased proliferation in response to mitogenic stimulation, and p50/RelA double knockout B cells exhibit greater defects in proliferation and class switching (Snapper et al, 1996b;Horwitz et al, 1999).…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Targeted removal of the C-terminal region of c-Rel, which contains the transactivation domain, leads to mice developing a complex phenotype of immune dysfunction that includes hypoplastic bone marrow, splenomegaly, enlarged lymph nodes and lymphoid hyperplasia (Carrasco et al, 1998). This truncated c-Rel protein is able to form dimers and bind DNA, but, like its viral counterpart v-Rel, is unlikely to be able to regulate the normal program of transcription.…”