title: Deletion of exon I of SMAD7 in mice results in altered B cell responses.
abstract: The members of the TGF-beta superfamily, i.e., TGF-beta 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-beta 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-beta 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-beta 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-beta 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-beta.
authors.affiliation: Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
authors.forename: Ronggui
authors.initials: R
authors.lastname: Li
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosendahl
authors.forename: Greger
authors.initials: G
authors.lastname: Brodin
authors.forename: Alec M
authors.initials: AM
authors.lastname: Cheng
authors.forename: Aive
authors.initials: A
authors.lastname: Ahgren
authors.forename: Christina
authors.initials: C
authors.lastname: Sundquist
authors.forename: Sarang
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Rainer L
authors.initials: RL
authors.lastname: Heuchel
mesh_terms: D016475:3T3 Cells; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D003433:Crosses, Genetic; D005091:Exons / Q000235:genetics*; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000235:genetics; D017578:Immunoglobulin Class Switching; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017384:Sequence Deletion; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D007070:Immunoglobulin A; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta