title: Asymmetric cell division during T cell development controls downstream fate.
abstract: During mammalian T cell development, the requirement for expansion of many individual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell division (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent divisions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal.
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Centre for Micro-Photonics, Faculty of Science, Engineering, and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Pham
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Centre for Micro-Photonics, Faculty of Science, Engineering, and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
authors.forename: Raz
authors.initials: R
authors.lastname: Shimoni
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Centre for Micro-Photonics, Faculty of Science, Engineering, and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia Industrial Research Institute Swinburne, Faculty of Science, Engineering, and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
authors.forename: Mirren
authors.initials: M
authors.lastname: Charnley
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Centre for Micro-Photonics, Faculty of Science, Engineering, and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: Ludford-Menting
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Edwin D
authors.initials: ED
authors.lastname: Hawkins
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Ramsbottom
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Jane
authors.initials: J
authors.lastname: Oliaro
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Izon
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Ting
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds LS2 9JT, England, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds LS2 9JT, England, UK.
authors.forename: Grant
authors.initials: G
authors.lastname: Lythe
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds, Leeds LS2 9JT, England, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Molina-Paris
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Heather
authors.initials: H
authors.lastname: Melichar
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Ellen
authors.initials: E
authors.lastname: Robey
authors.affiliation: Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Humbert
authors.affiliation: Centre for Micro-Photonics, Faculty of Science, Engineering, and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
authors.forename: Min
authors.initials: M
authors.lastname: Gu
authors.affiliation: Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia Centre for Micro-Photonics, Faculty of Science, Engineering, and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia sarah.russell@petermac.org.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Russell
mesh_terms: D033965:Adaptor Protein Complex alpha Subunits / Q000378:metabolism; D000818:Animals; D060049:Asymmetric Cell Division; D002450:Cell Communication; D016923:Cell Death; D002454:Cell Differentiation; D016764:Cell Polarity; D049109:Cell Proliferation; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D033965:Adaptor Protein Complex alpha Subunits; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011493:Protein Kinase C; D019718:Receptors, CXCR4; C527276:CXCR4 protein, human; C106293:Numb protein, mouse; C508433:scrib protein, mouse; C115015:PKC-3 protein