Maternal hypothyroidism selectively affects the expression of neuroendocrine-specific protein A messenger ribonucleic acid in the proliferative zone of the fetal rat brain cortex

Abstract

Thyroid hormone is essential for mammalian brain development, but the mechanisms by which thyroid hormone exerts its effects, the developmental processes affected, and the timing of thyroid hormone effects are poorly understood. An important question is whether thyroid hormone of maternal origin is essential in guiding fetal brain development. In both humans and rats, thyroid hormone of maternal origin reaches the fetus before the onset of fetal thyroid function. Moreover, receptors for thyroid hormone (TRs) are present in the fetal brain and are occupied by thyroid hormone. Finally, a recent report strongly indicates that transient undiagnosed maternal hypothyroidism can lead to measurable neurological deficits in the offspring despite the lack of neonatal hypothyroidism. Considering that TRs are ligand-activated transcription factors, we recently initiated a project to identify thyroid hormone-responsive genes in the fetal cortex before the onset of fetal thyroid function. One of the thyroid hormone-responsive genes we identified, neuroendocrine-specific protein (NSP), is expressed as two separate transcripts, NSP-A and NSP-C. Only NSP-A is affected by maternal thyroid hormone. We now demonstrate that the messenger RNA encoding NSP-A is expressed exclusively in the proliferative zone of the fetal cortex, and that its expression is affected by maternal hypothyroidism. Moreover, as development proceeds, NSP-A becomes selectively expressed in Purkinje cells of the cerebellum, a well known thyroid hormone-responsive cell. These findings strongly support the concept that thyroid hormone of maternal origin exerts specific receptor-mediated effects on fetal brain development.