title: MRTF-SRF signaling is required for seeding of HSC/Ps in bone marrow during development.
abstract: Chemokine signaling is important for the seeding of different sites by hematopoietic stem cells (HSCs) during development. Serum response factor (SRF) controls multiple genes governing adhesion and migration, mainly by recruiting members of the myocardin-related transcription factor (MRTF) family of G-actin-regulated cofactors. We used vav-iCre to inactivate MRTF-SRF signaling early during hematopoietic development. In both Srf- and Mrtf-deleted animals, hematopoiesis in fetal liver and spleen is intact but does not become established in fetal bone marrow. Srf-null HSC progenitor cells (HSC/Ps) fail to effectively engraft in transplantation experiments, exhibiting normal proximal signaling responses to SDF-1, but reduced adhesiveness, F-actin assembly, and reduced motility. Srf-null HSC/Ps fail to polarize in response to SDF-1 and cannot migrate through restrictive membrane pores to SDF-1 or Scf in vitro. Mrtf-null HSC/Ps were also defective in chemotactic responses to SDF-1. Srf-null HSC/Ps exhibit substantial deficits in cytoskeletal gene expression. MRTF-SRF signaling is thus critical for expression of genes required for the response to chemokine signaling during hematopoietic development.
authors.affiliation: Transcription Laboratory, and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Costello
authors.affiliation: Transcription Laboratory, and.
authors.forename: Mathew
authors.initials: M
authors.lastname: Sargent
authors.affiliation: Transcription Laboratory, and.
authors.forename: Diane
authors.initials: D
authors.lastname: Maurice
authors.affiliation: Transcription Laboratory, and.
authors.forename: Cyril
authors.initials: C
authors.lastname: Esnault
authors.affiliation: Haematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.
authors.forename: Katie
authors.initials: K
authors.lastname: Foster
authors.affiliation: Haematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.
authors.forename: Fernando
authors.initials: F
authors.lastname: Anjos-Afonso
authors.affiliation: Transcription Laboratory, and.
authors.forename: Richard
authors.initials: R
authors.lastname: Treisman
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000196:embryology* / Q000254:growth & development / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D026362:Serum Response Factor / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D055153:Stem Cell Niche / Q000235:genetics; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C511173:Mrtfa protein, mouse; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; C503315:myocardin-related transcription factor B, mouse