Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation.
The location of embryonic lymph node development is determined by the initial clustering of lymphoid tissue-inducer (LTi) cells. Here we demonstrate that both the chemokine CXCL13 and the chemokine CCL21 attracted LTi cells at embryonic days 12.5-14.5 and that initial clustering depended exclusively on CXCL13. Retinoic acid (RA) induced early CXCL13 expression in stromal organizer cells independently of lymphotoxin signaling. Notably, neurons adjacent to the lymph node anlagen expressed enzymes essential for RA synthesis. Furthermore, stimulation of parasymphathetic neural output in adults led to RA receptor (RAR)-dependent induction of CXCL13 in the gut. Therefore, our data show that the initiation of lymph node development is controlled by RA-mediated expression of CXCL13 and suggest that RA may be provided by adjacent neurons.
van de Pavert
Serge A
SA
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Olivier
Brenda J
BJ
Goverse
Gera
G
Vondenhoff
Mark F
MF
Greuter
Mascha
M
Beke
Patrick
P
Kusser
Kim
K
Höpken
Uta E
UE
Lipp
Martin
M
Niederreither
Karen
K
Blomhoff
Rune
R
Sitnik
Kasia
K
Agace
William W
WW
Randall
Troy D
TD
de Jonge
Wouter J
WJ
Mebius
Reina E
RE
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000196:embryology; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008198:Lymph Nodes / Q000196:embryology*; D008221:Lymphoid Tissue / Q000196:embryology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D050697:Retinal Dehydrogenase; D017154:Stromal Cells / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D055536:Vagus Nerve Stimulation
D054421:Chemokine CCL21; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D007527:Isoenzymes; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase