title: Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration.
abstract: Though aberrant neuronal migration in response to maternal thyroid hormone (TH) deficiency before the onset of fetal thyroid function (embryonic day [E] 17.5) in rat cerebral cortex has been described, molecular events mediating morphogenic actions have remained elusive. To investigate the effect of maternal TH deficiency on neocortical development, rat dams were maintained on methimazole from gestational day 6 until sacrifice. Decreased number and length of radial glia, loss of neuronal bipolarity, and impaired neuronal migration were correctible with early (E13-15) TH replacement. Reelin downregulation under hypothyroidism is neither due to enhanced apoptosis in Cajal-Retzius cells nor mediated through brain-derived neurotrophic factor-tyrosine receptor kinase B alterations. Results based on gel shift and chromatin immunoprecipitation assays show the transcriptional control of reelin by TH through the presence of intronic TH response element. Furthermore, hypothyroidism significantly increased TH receptor α1 with decreased reelin, apolipoprotein E receptor 2, very low-density lipoprotein receptor expression, and activation of cytosolic adapter protein disabled 1 that compromised the reelin signaling. Integrins (α(v) and β₁) are significantly decreased without alteration of α₃ indicating intact neuroglial recognition but disrupted adhesion and glial end-feet attachment. Results provide mechanistic basis of essentiality of adequate maternal TH levels to ensue proper fetal neocortical cytoarchitecture and importance of early thyroxine replacement.
authors.affiliation: Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226 014, India. madangodbole@yahoo.co.in
authors.forename: Amrita
authors.initials: A
authors.lastname: Pathak
authors.forename: Rohit Anthony
authors.initials: RA
authors.lastname: Sinha
authors.forename: Vishwa
authors.initials: V
authors.lastname: Mohan
authors.forename: Kalyan
authors.initials: K
authors.lastname: Mitra
authors.forename: Madan M
authors.initials: MM
authors.lastname: Godbole
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D005260:Female; D007037:Hypothyroidism / Q000196:embryology / Q000235:genetics / Q000473:pathology*; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000235:genetics; D019579:Neocortex / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013974:Thyroxine / Q000502:physiology* / Q000627:therapeutic use
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; D012697:Serine Endopeptidases; D013974:Thyroxine