title: Canonical BMP signaling is dispensable for hematopoietic stem cell function in both adult and fetal liver hematopoiesis, but essential to preserve colon architecture.
abstract: 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.
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University Hospital, Lund, Sweden.
authors.forename: Sofie
authors.initials: S
authors.lastname: Singbrant
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.forename: Karin
authors.initials: K
authors.lastname: Olsson
authors.forename: Pekka
authors.initials: P
authors.lastname: Jaako
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miharada
authors.forename: Matthias
authors.initials: M
authors.lastname: Stadtfeld
authors.forename: Thomas
authors.initials: T
authors.lastname: Graf
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
mesh_terms: 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
chemical_list: D019485:Bone Morphogenetic Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D052004:Bone Morphogenetic Protein Receptors