TY - JOUR
T1 - Involvement of neurons and retinoic acid in lymphatic development
T2 - New insights in increased nuchal translucency
AU - Burger, Nicole B.
AU - Stuurman, Kyra E.
AU - Kok, Evelien
AU - Konijn, Tanja
AU - Schooneman, Dennis
AU - Niederreither, Karen
AU - Coles, Mark
AU - Agace, William W.
AU - Christoffels, Vincent M.
AU - Mebius, Reina E.
AU - van de Pavert, Serge A.
AU - Bekker, Mireille N.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Objective: Increased nuchal translucency originates from disturbed lymphatic development. Abnormal neural crest cell (NCC) migration may be involved in lymphatic development. Because both neuronal and lymphatic development share retinoic acid (RA) as a common factor, this study investigated the involvement of NCCs and RA in specific steps in lymphatic endothelial cell (LEC) differentiation and nuchal edema, which is the morphological equivalent of increased nuchal translucency. Methods: Mouse embryos in which all NCCs were fluorescently labeled (Wnt1-Cre;Rosa26eYfp), reporter embryos for in vivo RA activity (DR5-luciferase) and embryos with absent (Raldh2-/-) or in utero inhibition of RA signaling (BMS493) were investigated. Immunofluorescence using markers for blood vessels, lymphatic endothelium and neurons was applied. Flow cytometry was performed to measure specific LEC populations. Results: Cranial nerves were consistently close to the jugular lymph sac (JLS), in which NCCs were identified. In the absence of RA synthesis, enlarged JLS and nuchal edema were observed. Inhibiting RA signaling in utero resulted in a significantly higher amount of precursor-LECs at the expense of mature LECs and caused nuchal edema. Conclusions: Neural crest cells are involved in lymphatic development. RA is required for differentiation into mature LECs. Blocking RA signaling in mouse embryos results in abnormal lymphatic development and nuchal edema.
AB - Objective: Increased nuchal translucency originates from disturbed lymphatic development. Abnormal neural crest cell (NCC) migration may be involved in lymphatic development. Because both neuronal and lymphatic development share retinoic acid (RA) as a common factor, this study investigated the involvement of NCCs and RA in specific steps in lymphatic endothelial cell (LEC) differentiation and nuchal edema, which is the morphological equivalent of increased nuchal translucency. Methods: Mouse embryos in which all NCCs were fluorescently labeled (Wnt1-Cre;Rosa26eYfp), reporter embryos for in vivo RA activity (DR5-luciferase) and embryos with absent (Raldh2-/-) or in utero inhibition of RA signaling (BMS493) were investigated. Immunofluorescence using markers for blood vessels, lymphatic endothelium and neurons was applied. Flow cytometry was performed to measure specific LEC populations. Results: Cranial nerves were consistently close to the jugular lymph sac (JLS), in which NCCs were identified. In the absence of RA synthesis, enlarged JLS and nuchal edema were observed. Inhibiting RA signaling in utero resulted in a significantly higher amount of precursor-LECs at the expense of mature LECs and caused nuchal edema. Conclusions: Neural crest cells are involved in lymphatic development. RA is required for differentiation into mature LECs. Blocking RA signaling in mouse embryos results in abnormal lymphatic development and nuchal edema.
UR - https://www.scopus.com/pages/publications/84918512306
U2 - 10.1002/pd.4473
DO - 10.1002/pd.4473
M3 - Article
C2 - 25088217
AN - SCOPUS:84918512306
SN - 0197-3851
VL - 34
SP - 1312
EP - 1319
JO - Prenatal Diagnosis
JF - Prenatal Diagnosis
IS - 13
ER -