Project 1: Thyroid Hormone and Brain Development
Thyroid hormone is clearly essential for normal brain development. However, the mechanisms by which thyroid hormone exerts its effects, and the timing of thyroid hormone action, remain unclear. There is considerable evidence that maternal thyroid hormone can affect fetal brain development, but several questions remain. We have begun to look at this issue in a unique way - by cloning genes expressed in the fetal brain that are regulated by thyroid hormone before the onset of fetal thyroid function.
The lab is engaged in several projects to clarify the role of thyroid hormone in early brain development and to identify the molecular and cellular mechanisms by which thyroid hormone exerts its effects. These projects are broadly outlined below.
Considering that thyroid hormone receptors (TRs) are ligand-activated transcription factors, we have sought to identify thyroid hormone responsive genes in the fetal cortex before the fetal thyroid begins to function on gestational day 17. Identification of such genes would simultaneously support the concept that thyroid hormone of maternal origin can directly affect early cortical development and provide clues about the developmental events affected by thyroid hormone. We have used two approaches to identify these genes. The first, shown to the left is a mRNA differential display performed by Amy Dowling (Dowling et al., J. Neurosci. 2000, 20(6):2255-2265).
Thyroid hormone is known to stimulate cell proliferation in some systems. In addition, thyroid hormone increases the proliferation of cells in the developing cerebellum. Therefore, we considered the possibility that maternal thyroid hormone is regulating proliferation in the fetal cortex. However, we could find no evidence for this. However, we did find that thyroid hormone regulates the expression of a gene (HES-1) thought to be involved in gliogenesis. We are now pursuing the concept that thyroid hormone shifts the balance of production of nerve cells and glia early in development.