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Brenda L. Bohnsack, Alon Kahana; Neural Crest Cells Respond To Dynamic Changes In Thyroid Hormone And Retinoic Acid Signaling During Embryogenesis: Implications For Pathogenesis Of Thyroid Eye Disease. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2222.
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© ARVO (1962-2015); The Authors (2016-present)
Thyroid eye disease (TED) has significant morbidity due to vision loss, strabismus, and disfigurement, propagated by autoimmune inflammation. However, the biological trigger remains unknown. We hypothesized that cranial neural crest (CNC)-derived orbital fibroblasts are innately sensitive to thyroid hormone (TH) changes, which we tested using a zebrafish embryo model.
We used transgenic zebrafish expressing GFP in CNC cells. Exogenous regulators and analogs of TH, retinoic acid (RA) receptors (RAR) and retinoid X receptors (RXR) were used in combination with antisense knockdown of TH receptor (THR) and deiodinase enzymes (dio2-to reduce synthesis; dio3-to block degradation). Embryos were imaged and harvested for in situ hybridization, immunostaining, TUNEL assay, and ocular histology.
Pharmacologic and genetic alterations in TH signaling disrupted CNC development causing ocular and craniofacial defects (F vs E). TH regulated migration, proliferation and survival of CNC that populate the eye and periocular mesenchyme. Ventral CNC required THR, but sustained TH inhibited migration completion. Since THR and RAR dimerize with RXR, we tested if RA interacted with TH. We found that low level of RA rescued TH loss (B), but worsened the phenotype of sustained excess TH. TH and RA differentially regulated pharyngeal arch formation, revealing a reciprocal relationship between TH and RA that is mediated in part by RXR (D) and regulates pitx2 and twist1 expression.
Our results reveal that orbitocranial CNC development requires TH. CNC cells respond differently to sustained versus dynamic TH levels. Interaction between TH and RA in tissue microenvironment suggests that CNC-derived orbital fibroblasts may have a distinct response (i.e. "trigger") to dynamic TH levels in the context of TED: in the presence of high orbital RA, changes in TH can reactivate embryologic pathways that induce proliferation, transdifferentiation, and cytokine release which in the autoimmune milieu of TED results in "propagation." These findings suggest that RA analogues may stop disease trigger. Further work is required to assess if these findings apply to human tissues.
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