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Deletion of Exon I of SMAD7 in Mice Results in Altered B Cell Responses

Ronggui Li^1,2,*, Alexander Rosendahl^1,, Greger Brodin^1,*, Alec M. Cheng^3,, Aive Ahgren^*, Christina Sundquist^*, Sarang Kulkarni, Tony Pawson, Carl-Henrik Heldin^* and Rainer L. Heuchel^4,*

^* Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden; AstraZeneca R&D Lund, Department of Biological Sciences, Lund, Sweden; Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada; and Department of Medicine, Washington University, School of Medicine, St. Louis, MO 63110

The members of the TGF- superfamily, i.e., TGF- isoforms, activins, and bone morphogenetic proteins, regulate growth, differentiation, and apoptosis, both during embryonic development and during postnatal life. Smad7 is induced by the TGF- superfamily members and negatively modulates their signaling, thus acting in a negative, autocrine feedback manner. In addition, Smad7 is induced by other stimuli. Thus, it can fine-tune and integrate TGF- signaling with other signaling pathways. To investigate the functional role(s) of Smad7 in vivo, we generated mice deficient in exon I of Smad7, leading to a partial loss of Smad7 function. Mutant animals are viable, but significantly smaller on the outbred CD-1 mouse strain background. Mutant B cells showed an overactive TGF- signaling measured as increase of phosphorylated Smad2-positive B cells compared with B cells from wild-type mice. In agreement with this expected increase in TGF- signaling, several changes in B cell responses were observed. Mutant B cells exhibited increased Ig class switch recombination to IgA, significantly enhanced spontaneous apoptosis in B cells, and a markedly reduced proliferative response to LPS stimulation. Interestingly, LPS treatment reverted the apoptotic phenotype in the mutant cells. Taken together, the observed phenotype highlights a prominent role for Smad7 in development and in regulating the immune system’s response to TGF-.

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