Normal erythropoiesis but severe polyposis and bleeding anemia in Smad4-deficient mice.
The tumor suppressor Smad4 mediates signaling by the transforming growth factor beta (TGF-beta) superfamily of ligands. Previous studies showed that several TGF-beta family members exert important functions in hematopoiesis. Here, we studied the role of Smad4 in adult murine hematopoiesis using the inducible Mx-Cre/loxP system. Mice with homozygous Smad4 deletion (Smad4(Delta/Delta)) developed severe anemia 6 to 8 weeks after induction (mean hemoglobin level 70 g/L). The anemia was not transplantable, as wild-type mice reconstituted with Smad4(Delta/Delta) bone marrow cells had normal peripheral blood counts. These mice did not develop an inflammatory disease typical for mice deficient in TGF-beta receptors I and II, suggesting that the suppression of inflammation by TGF-beta is Smad4 independent. The same results were obtained when Smad4 alleles were deleted selectively in hematopoietic cells using the VavCre transgenic mice. In contrast, lethally irradiated Smad4(Delta/Delta) mice that received wild-type bone marrow cells developed anemia similar to Smad4(Delta/Delta) mice that did not receive a transplant. Liver iron stores were decreased and blood was present in stool, indicating that the anemia was due to blood loss. Multiple polyps in stomach and colon represent a likely source of the bleeding. We conclude that Smad4 is not required for adult erythropoiesis and that anemia is solely the consequence of blood loss.
Pan
Dejing
D
Department of Research, Experimental Hematology, University Hospital Basel, Basel, Switzerland.
Schomber
Tibor
T
Kalberer
Christian P
CP
Terracciano
Luigi M
LM
Hafen
Katrin
K
Krenger
Werner
W
Hao-Shen
Hui
H
Deng
Chuxia
C
Skoda
Radek C
RC
D000740:Anemia / Q000209:etiology*; D000818:Animals; D016026:Bone Marrow Transplantation; D004920:Erythropoiesis / Q000502:physiology*; D005434:Flow Cytometry; D006471:Gastrointestinal Hemorrhage / Q000209:etiology*; D044483:Intestinal Polyposis / Q000209:etiology* / Q000473:pathology; D000090463:Iron Deficiencies; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011127:Polyps / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051901:Smad4 Protein / Q000172:deficiency*; D013272:Stomach Diseases / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta