title: The essential function for serum response factor in T-cell development reflects its specific coupling to extracellular signal-regulated kinase signaling.
abstract: Serum response factor (SRF) recruits members of two families of signal-regulated coactivators, the extracellular signal-regulated kinase (ERK)-regulated ternary complex factors (TCFs) and the actin-regulated myocardin-related transcription factors (MRTFs), to its target genes through its DNA-binding domain. Whether coactivator association is required for SRF function in vivo and whether particular SRF functions reflect specific coupling to one or the other signal pathway have remained largely unexplored. We show that SRF is essential for thymocyte positive selection and thymic T(reg) and NK T-cell development but dispensable for early thymocyte development and negative selection. Expression of wild-type SRF, or mutants lacking the N-terminal phosphorylation sites or C-terminal transcriptional activation domain, restores positive selection in SRF null thymocytes. In contrast, SRF.V194E, which cannot recruit TCF or MRTF family members, is inactive, although it is recruited to target genes. Fusion of a TCF C-terminal activation domain to SRF.V194E effectively restores ERK-dependent single-positive (SP) thymocyte development. The resulting SP thymocytes exhibit normal surface marker expression and proliferation following T-cell receptor cross-linking. Thus, ERK signaling through the TCF pathway to SRF is necessary and sufficient for SRF function in thymocyte positive selection.
authors.affiliation: Transcription Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3LY, United Kingdom.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Mylona
authors.forename: Robert
authors.initials: R
authors.lastname: Nicolas
authors.forename: Diane
authors.initials: D
authors.lastname: Maurice
authors.forename: Mathew
authors.initials: M
authors.lastname: Sargent
authors.forename: David
authors.initials: D
authors.lastname: Tuil
authors.forename: Dominique
authors.initials: D
authors.lastname: Daegelen
authors.forename: Richard
authors.initials: R
authors.lastname: Treisman
authors.forename: Patrick
authors.initials: P
authors.lastname: Costello
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D007694:Killer Cells, Natural / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D011993:Recombinant Fusion Proteins; D026362:Serum Response Factor; D051820:TCF Transcription Factors; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases