Canonical BMP signaling is dispensable for hematopoietic stem cell function in both adult and fetal liver hematopoiesis, but essential to preserve colon architecture.
Numerous publications have described the importance of bone morphogenetic protein (BMP) signaling in the specification of hematopoietic tissue in developing embryos. Here we investigate the full role of canonical BMP signaling in both adult and fetal liver hematopoiesis using conditional knockout strategies because conventional disruption of components of the BMP signaling pathway result in early death of the embryo. By targeting both Smad1 and Smad5, we have generated a double-knockout mouse with complete disruption of canonical BMP signaling. Interestingly, concurrent deletion of Smad1 and Smad5 results in death because of extrahematopoietic pathologic changes in the colon. However, Smad1/Smad5-deficient bone marrow cells can compete normally with wild-type cells and display unaffected self-renewal and differentiation capacity when transplanted into lethally irradiated recipients. Moreover, although BMP receptor expression is increased in fetal liver, fetal liver cells deficient in both Smad1 and Smad5 remain competent to long-term reconstitute lethally irradiated recipients in a multilineage manner. In conclusion, canonical BMP signaling is not required to maintain either adult or fetal liver hematopoiesis, despite its crucial role in the initial patterning of hematopoiesis in early embryonic development.
Singbrant
Sofie
S
Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University Hospital, Lund, Sweden.
Karlsson
Göran
G
Ehinger
Mats
M
Olsson
Karin
K
Jaako
Pekka
P
Miharada
Ken-Ichi
K
Stadtfeld
Matthias
M
Graf
Thomas
T
Karlsson
Stefan
S
D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000096:biosynthesis / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D003106:Colon / Q000196:embryology / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism; D005333:Fetus / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006411:Hematopoiesis, Extramedullary / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008099:Liver / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D014184:Transplantation, Homologous
D019485:Bone Morphogenetic Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D052004:Bone Morphogenetic Protein Receptors