Submitted February 20, 2007
Accepted July 3, 2007
Normal erythropoiesis but severe polyposis and bleeding anemia in Smad4 deficient mice
Dejing Pan, Tibor Schomber, Christian P Kalberer, Luigi M Terracciano, Katrin Hafen, Werner Krenger, Hui Hao-Shen, Chuxia Deng, and Radek C Skoda*
Department of Research, Experimental Hematology, University Hospital Basel, Basel, Switzerland
Department of Pathology, University Hospital Basel and Department of Health Sciences, University of Molise, Campobasso, Italy
Department of Clinical-Biological Sciences, Laboratory of Pediatric Immunology, University of Basel, and Basel University Children's Hospital, Basel, Switzerland
Mammalian Genetics Section, Genetics of Development & Disease Branch, NIDDK, NIH, Bethesda, MD, United States
* Corresponding author; email: radek.skoda{at}unibas.ch.
The tumor suppressor Smad4 mediates signaling by transforming growth factor-beta (TGF-
) superfamily of ligands. Previous studies showed that several TGF- 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
/) developed severe anemia 6-8 weeks after induction (mean hemoglobin 70g/L). The anemia was not transplantable, as wild type mice reconstituted with Smad4/ bone marrow cells had normal peripheral blood counts. These mice did not develop an inflammatory disease typical for mice deficient in TGF- receptors I and II suggesting that the suppression of inflammation by TGF- is Smad4 independent. The same results were obtained when Smad4 alleles were deleted seletively in hematopoietic cells using the VavCre transgenic mice. In contrast, lethally irradiated Smad4/ mice transplanted with wild type bone marrow cells developed anemia similar to non-transplanted Smad4/ mice. 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.
