title: Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption.
abstract: Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of 'neurometabolic' integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2-/-mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2-/-(GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker,Troma-I(cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical 'organ',i.e. 'parathymic lobes'. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe - suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature 'aging' phenotype of GIT2KO mice.
authors.affiliation: Receptor Pharmacology Unit, Laboratory of Neurosciences, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD 21224, USA.
authors.forename: Sana
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: Laboratory of Molecular Biology and Immunology, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Lustig
authors.affiliation: Laboratory of Molecular Biology and Immunology, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Arnell
authors.initials: A
authors.lastname: Carter
authors.affiliation: Metabolism Unit, Laboratory of Clinical Investigation, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Mathavi
authors.initials: M
authors.lastname: Sankar
authors.affiliation: Metabolism Unit, Laboratory of Clinical Investigation, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Daimon
authors.affiliation: Duke University Medical Center, Durham, NC 27705, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Premont
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium.
authors.forename: Harmonie
authors.initials: H
authors.lastname: Etienne
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium.
authors.forename: Jaana
authors.initials: J
authors.lastname: van Gastel
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium.
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Azmi
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Janssens
authors.affiliation: Gene Expression and Genomics Unit, Research Resources Branch, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: Gene Expression and Genomics Unit, Research Resources Branch, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Gene Expression and Genomics Unit, Research Resources Branch, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wood
authors.affiliation: Gene Expression and Genomics Unit, Research Resources Branch, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.affiliation: Research Institute of the MUHC, Centre for Translational Biology (CTB), Meakins-Christie Laboratories, McGill University, Montreal, QC, H4A 3J1, Canada.
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
authors.affiliation: Metabolism Unit, Laboratory of Clinical Investigation, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.affiliation: Laboratory of Molecular Biology and Immunology, NIA, NIH, Baltimore, MD 21224, USA.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Taub
authors.affiliation: Receptor Pharmacology Unit, Laboratory of Neurosciences, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD 21224, USA.|Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
mesh_terms: D000375:Aging / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D019588:Aging, Premature / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D020690:GTPase-Activating Proteins; D007107:Immune System / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins; D053533:Keratin-8 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013950:Thymus Gland / Q000276:immunology / Q000503:physiopathology*; D059467:Transcriptome
chemical_list: D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; C120767:Git2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D053533:Keratin-8; C486595:Krt8 protein, mouse; D010750:Phosphoproteins
keywords: CXCR4; GIT2; T cell differentiation; aging; bioinformatics; clock; metabolism; thymic involution