title: SWEF Proteins Distinctly Control Maintenance and Differentiation of Hematopoietic Stem Cells.
abstract: SWAP-70 and DEF6, two proteins that feature similar domain and motif arrangements, are mainly known for their functions in differentiated hematopoietic cells. Both proteins interact with and regulate RhoGTPases and F-actin dynamics, yet their role in hematopoietic stem and precursor cells (HSPCs) remained unexplored. Here, the role of the SWEF proteins SWAP-70 and DEF6 in HSPCs was examined. Both SWEF proteins are expressed in HSCs. HSCs and different precursor populations were analyzed in mice deficient for SWAP-70, DEF6, SWAP-70 and DEF6 (double knockout, DKO), and wild-type controls. HSPCs isolated from these strains were used for competitive adoptive transfer into irradiated wild-type mice. Reconstitution of the myeloid and lymphoid lineages in the recipient mice was determined. The numbers of HSPCs in the bone marrow of Swap-70-/- and Swap-70-/-Def6-/- mice were >3-fold increased. When transplanted into lethally irradiated wild-type recipients, the reconstitution potential of Swap-70-/- HSPCs was intrinsically impaired in competing with wild-type HSPCs for contribution to hematopoiesis. Def6-/- HSPCs show wild type-like reconstitution potential under the same transplantation conditions. DKO HSPCs reconstituted to only 25% of wild-type levels, indicating a partial rescue by DEF6 deficiency in the Swap-70-/- background. Our study reveals the two SWEF proteins as important contributors to HSPC biology. Despite their similarity these two proteins regulate HSC/progenitor homeostasis, self-renewal, lineage contributions and repopulation in a distinct and mostly antagonistic manner.
authors: Institute of Physiological Chemistry, Technische Universität Dresden, 01307, Dresden, Germany.
authors: Tatsiana
authors: T
authors: Ripich
authors: Institute of Physiological Chemistry, Technische Universität Dresden, 01307, Dresden, Germany.
authors: Carlos Andrés
authors: CA
authors: Chacón-Martínez
authors: Osteoimmunology, CRTD, Technische Universität Dresden, 01307, Dresden, Germany.
authors: Luise
authors: L
authors: Fischer
authors: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY, 10021, United States of America.
authors: Alessandra
authors: A
authors: Pernis
authors: Institute of Physiological Chemistry, Technische Universität Dresden, 01307, Dresden, Germany.
authors: Nadine
authors: N
authors: Kiessling
authors: Institute of Physiological Chemistry, Technische Universität Dresden, 01307, Dresden, Germany.
authors: Annette I
authors: AI
authors: Garbe
authors: Institute of Physiological Chemistry, Technische Universität Dresden, 01307, Dresden, Germany.
authors: Rolf
authors: R
authors: Jessberger
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D001853:Bone Marrow / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002469:Cell Separation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D000199:Actins; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; C473249:Def6 protein, mouse; C113365:Swap70 protein, mouse