Maternal Thyroid Hormone before the Onset of Fetal Thyroid Function Regulates Reelin and Downstream Signaling Cascade Affecting Neocortical Neuronal Migration

作者：Pathak Amrita; Sinha Rohit Anthony; Mohan Vishwa; Mitra Kalyan; Godbole Madan M^*

来源：Cerebral Cortex, 2011, 21(1): 11-21.

DOI：10.1093/cercor/bhq052

• development
• integrin
• neocortex
• neuronal migration
• reelin

Though aberrant neuronal migration in response to maternal thyroid hormone (TH) deficiency before the onset of fetal thyroid 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 alpha 1 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 (alpha(v) and beta(1)) are significantly decreased without alteration of alpha(3) 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.

• 出版日期2011-1
• 单位河北医科大学