title: Ectopic cross-talk between thyroid and retinoic acid signaling: A possible etiology for spinal neural tube defects.
abstract: Previous studies have highlighted the connections between neural tube defects (NTDs) and both thyroid hormones (TH) and vitamin A. However, whether the two hormonal signaling pathways interact in NTDs has remained unclear. We measured the expression levels of TH signaling genes in human fetuses with spinal NTDs associated with maternal hyperthyroidism as well as levels of retinoic acid (RA) signaling genes in mouse fetuses exposed to an overdose of RA using NanoString or real-time PCR on spinal cord tissues. Interactions between the two signaling pathways were detected by ChIP assays. The data revealed attenuated DIO2/DIO3 switching in fetuses with NTDs born to hyperthyroid mothers. The promoters of the RA signaling genes CRABP1 and RARB were ectopically occupied by increased RXRG and RXRB but displayed decreased levels of inhibitory histone modifications, suggesting that elevated TH signaling abnormally stimulates RA signaling genes. Conversely, in the mouse model, the observed decrease in Dio3 expression could be explained by increased levels of inhibitory histone modifications in the Dio3 promoter region, suggesting that overactive RA signaling may ectopically derepress TH signaling. This study thus raises in vivo a possible abnormal cross-promotion between two different hormonal signals through their common RXRs and the subsequent recruitment of histone modifications, prompting further investigation into their involvement in the etiology of spinal NTDs.
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China. Electronic address: lihuili2011@gmail.com.
authors.forename: Huili
authors.initials: H
authors.lastname: Li
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China.
authors.forename: Baoling
authors.initials: B
authors.lastname: Bai
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Guo
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China.
authors.forename: Chunyue
authors.initials: C
authors.lastname: Miao
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Liu
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China. Electronic address: zhangtingcv@126.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism; D009436:Neural Tube Defects / Q000097:blood* / Q000235:genetics; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood* / Q000235:genetics; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D013963:Thyroid Hormones / Q000097:blood*; D014212:Tretinoin / Q000097:blood*
chemical_list: D006657:Histones; D013963:Thyroid Hormones; D014212:Tretinoin; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase
keywords: Histone modification; Neural tube defect; Retinoic acid signaling; Retinoid X receptor; Thyroid signaling