title: Thyroid hormone promotes neuronal differentiation of embryonic neural stem cells by inhibiting STAT3 signaling through TRα1.
abstract: A deficiency of maternal thyroid hormones (THs) during pregnancy may have severe impacts on fetal brain development. However, the cellular targets of THs and their underlying mechanisms are still unclear. In this study, we found that maternal hypothyroidism during pregnancy in mice inhibited neurogenesis in the embryonic telencephalon and caused learning and memory impairment in the offspring. To explore the underlying mechanisms, we treated cultured mouse embryonic neural stem cells (eNSCs) with a physiological level of 3, 5, 3'-triiodo-L-thyronine (T3). We found that T3 promoted the neuronal differentiation of eNSCs, while inhibiting astrocytic differentiation. In addition, the proliferation and maintenance of eNSCs were inhibited by T3. Furthermore, the TH receptor alpha 1 (TRα1) was detected in the eNSCs both in vivo and in vitro. Silencing TRα1 protein expression with specific siRNA eliminated the effects of T3 on eNSCs. We also found that T3 decreased STAT3 phosphorylation and STAT3-DNA binding activity through TRα1. The over expression of STAT3 attenuated the promotive effects of T3 on neuronal differentiation of eNSCs. Taken together, these results suggest that T3 promotes the neuronal differentiation of eNSCs by inhibiting STAT3 signaling activity through TRα1 and contributes to early neurogenesis in the embryonic telencephalon. Our studies reveal the physiological effects of TH in regulating eNSCs differentiation and suggest that eNSCs are one of the major cellular targets in the central nervous system by which TH influences early brain development. These findings also provide new insights into the mechanisms of neurological deficits caused by TH deficiency during embryogenesis.
authors.affiliation: Department of Occupational Health, Faculty of Preventive Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Chunhai
authors.initials: C
authors.lastname: Chen
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Maoquan
authors.initials: M
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Mingyue
authors.initials: M
authors.lastname: Qu
authors.forename: Ju
authors.initials: J
authors.lastname: Yang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D007037:Hypothyroidism / Q000139:chemically induced; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D055495:Neurogenesis; D010766:Phosphorylation; D011247:Pregnancy; D011441:Propylthiouracil / Q000008:administration & dosage / Q000009:adverse effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013687:Telencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D037021:Thyroid Hormone Receptors alpha; D014284:Triiodothyronine; D011441:Propylthiouracil