Maternal Thyroid Hormone: A Strong Repressor of Neuronal Nitric Oxide Synthase in Rat Embryonic Neocortex

Abstract

Understanding of how maternal thyroid inadequacy during early gestation poses a risk for developmental outcomes is still a challenge for the neuroendocrine community. Early neocortical neurogenesis is accompanied by maternal thyroid hormone (TH) transfer to fetal brain, appearance of TH receptors, and absence of antineurogenesis signals, followed by optimization of neuronal numbers through apoptosis. However, the effects of TH deprivation on neurogenesis and neuronal cell death before the onset of fetal thyroid are still not clear. We show that maternal TH deficiency during early gestational period causes massive premature elevation in the expression of neuronal nitric oxide synthase (nNOS) with an associated neuronal death in embryonic rat neocortex. Maternal hypothyroidism was induced by feeding methimazole (0.025% wt/vol) in the drinking water to pregnant Sprague Dawley rats from embryonic d 6. Cerebral cortices from fetuses were harvested at different embryonic stages (embryonic d 14, 16, and 18) of hypothyroid and euthyroid groups. Immunoblotting and real-time PCR results showed that both protein and RNA levels of nNOS were prematurely increased under maternal hypothyroidism, and showed reversibility upon T4 administration. Immunohistochemistry revealed an increased nNOS immunoreactivity in both the cortical plate and proliferative zone of neocortex along with a corroborative decrease in the microtubule associated protein-2 positive neurons under maternal TH insufficiency. Results combined, put forth nNOS as a novel target of maternal TH action in embryonic neocortex, and underscore the importance of prenatal screening and timely rectification of maternal TH insufficiency, even of a moderate degree.

Thyroid Hormone Regulation of Gene Expression in the Developing Rat Fetal Cerebral Cortex: Prominent Role of the Ca2+/Calmodulin-Dependent Protein Kinase IV Pathway

“…In fact, studies using models of maternal and fetal hypothyroidism as employed in this work have identified genes that were sensitive to thyroid hormones in the postnatal brain but insensitive in the late fetal brain (32). Other studies have shown quantitative changes in specific mRNAs or proteins after maternal hypothyroidism or thyroid hormone treatment (17), but a global analysis of the effect of thyroid hormones on the fetal brain has not been made.…”

“…The molecular basis for these alterations remains unknown and may consist of subtle actions, probably restricted to specific cellular groups. Maternal thyroid hormones should also be important at earlier stages of gestation and especially before onset of fetal thyroid hormone secretion (16,17) or in situations of isolated fetal hypothyroidism. The experimental approach and the molecular targets described in this paper are valuable tools to investigate this issue in more detail.…”

“…Although the developmental timing of cerebral and cerebellar cortices is different, it raises the possibility that the consequences of thyroid hormone deprivation for fetal brain development might be due to indirect causes unrelated to the genomic actions of thyroid hormone. Further efforts to identify genes regulated by thyroid hormones in the fetal brain have met with limited success (16,17).…”

Evaluation of the BDNF, NGF, NT3 and NT4 Genes Expressions in the Brains of Neonatal Mice with Hypothyroidism

“…Thyroid hormones have an important role in differentiation of oligodendrocytes and cause defects in axonal maturation . Evaluation of culture of fetal neurons revealed that thyroid hormones play a role in regulation of gene expression in fetal brain in utero (Sinha, 2008).…”

Thyroid Hormone Level Positively Regulates NOS and cGMP in the Developing Rat Cerebellum

“…Up to now, only a small number of studies have dealt with the possible interaction of TH and NO in the CNS, showing downregulation of nNOS expression in the embryonic cerebral cortex [22], but upregulation of nNOS expression in the postnatal cerebral cortex [23], in the adult hypothalamus [24], and enhanced nNOS activity in adult cortical synaptosomes [25] followed by the elevation of T 3 level. On the other hand, in recent non-neural studies, more attention was paid to hyperthyroidism-induced NOS-dependent vasodilatation [for review, see [26]].…”