title: Absence of Rac1 and Rac3 GTPases in the nervous system hinders thymic, splenic and immune-competence development.
abstract: The nervous system influences organ development by direct innervation and the action of hormones. We recently showed that the specific absence of Rac1 in neurons (Rac1(N) ) in a Rac3-deficient (Rac3(KO) ) background causes motor behavioural defects, epilepsy, and premature mouse death around postnatal day 13. We report here that Rac1(N) /Rac3(KO) mice display a progressive loss of immune-competence. Comparative longitudinal analysis of lymphoid organs from control, single Rac1(N) or Rac3(KO) , and double Rac1(N) /Rac3(KO) mutant animals showed that thymus development is preserved up to postnatal day 9 in all animals, but is impaired in Rac1(N) /Rac3(KO) mice at later times. This is evidenced by a drastic reduction in thymic cell numbers. Cell numbers were also reduced in the spleen, leading to splenic tissue disarray. Organ involution occurs in spite of unaltered thymocyte and lymphocyte subset composition, and proper mature T-cell responses to polyclonal stimuli in vitro. Suboptimal thymus innervation by tau-positive neuronal terminals possibly explains the suboptimal thymic output and arrested thymic development, which is accompanied by higher apoptotic rates. Our results support a role for neuronal Rac1 and Rac3 in dictating proper lymphoid organ development, and suggest the existence of lymphoid-extrinsic mechanisms linking neural defects to the loss of immune-competence.
authors.affiliation: Lymphocyte Activation Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Basso
authors.forename: Sara
authors.initials: S
authors.lastname: Corbetta
authors.forename: Sara
authors.initials: S
authors.lastname: Gualdoni
authors.forename: Diletta
authors.initials: D
authors.lastname: Tonoli
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
authors.forename: Ivan
authors.initials: I
authors.lastname: de Curtis
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D007121:Immunocompetence; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000254:growth & development / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development / Q000276:immunology* / Q000294:innervation; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C498771:Rac3 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein