title: Transient Maternal Hypothyroxinemia Potentiates the Transcriptional Response to Exogenous Thyroid Hormone in the Fetal Cerebral Cortex Before the Onset of Fetal Thyroid Function: A Messenger and MicroRNA Profiling Study.
abstract: Thyroid hormone (TH) is essential for brain development both before and after birth. We have used gene expression microarrays to identify TH-regulated genes in the fetal cerebral cortex prior to the onset of fetal thyroid function to better understand the role of TH in early cortical development. TH levels were transiently manipulated in pregnant mice by treatment with goitrogens from gestational day (GD) 13-16 and/or by injection of TH 12 h before sacrifice on GD 16. The transcriptional response to exogenous TH in the GD 16 fetal cortex was potentiated by transient goitrogen treatment, suggesting that the hypothyroxinemic brain is a different substrate upon which TH can act, or that robust compensatory mechanisms are induced by transient hypothyroxinemia. Several known TH-responsive genes were identified including Klf9, and several novel TH-responsive genes such as Appbp2, Ppap2b, and Fgfr1op2 were identified in which TH response elements were confirmed. We also identified specific microRNAs whose expression in the fetal cortex was affected by TH treatment, and determined that Ppap2b and Klf9 are the target genes of miR-16 and miR-106, respectively. Thus, a complex redundant functional network appears to coordinate TH-mediated gene expression in the developing brain.
authors.affiliation: Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada K1A 0K9.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Biology and Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003, USA Current address: Cardiovascular and Metabolism Therapeutic Area, Janssen Pharmaceutical Companies of Johnson & Johnson, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Seo-Hee
authors.initials: SH
authors.lastname: You
authors.affiliation: Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada K1A 0K9.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada K1A 0K9.
authors.forename: Mike G
authors.initials: MG
authors.lastname: Wade
authors.affiliation: Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, ON, Canada K1A 0K9.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
authors.affiliation: Department of Biology and Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: R
authors.initials: R
authors.lastname: Thomas Zoeller
mesh_terms: D000208:Acute Disease; D000818:Animals; D013956:Antithyroid Agents; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007037:Hypothyroidism / Q000097:blood*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D009447:Neuroblastoma / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D014158:Transcription, Genetic
chemical_list: D013956:Antithyroid Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D013963:Thyroid Hormones; D013974:Thyroxine
keywords: Klf9; brain development; methimazole; miR-106; microarray