Non-genomic actions of thyroid hormone in brain development

Abstract

Thyroid hormone (TH) is essential for neuronal migration and synaptogenesis in the developing brain. Assembly of neuronal circuits depends on guidance cues provided by the extracellular matrix. These cues are interpreted by the migrating neuron and its growing neurites through transmembrane signaling proteins anchored in place by the actin cytoskeleton. One of the best examples of a non-genomic action of thyroid hormone is its dynamic regulation of the number and quantity of actin fibers in astrocytes. Thyroxine (T4) and its transcriptionally inactive metabolite, 3',5',3-triiodothyronine (reverse T3) are responsible for modulating microfilament organization, while the transcriptional activator, 3',3,5-triiodothyronine (T3) is inert. The biological consequence of the loss of the actin filaments in astrocytes is the inability of the cell to anchor laminin, to its cell surface, and the loss of this key guidance molecule interrupts neurite pathfinding and neuronal migration. These data provide the essentials to construct a physiological pathway where TH-dependent regulation of the polymerization state of actin in the astrocyte and the developing neuron modulates the production and recognition of guidance cues--cues that if disrupted lead to abnormal neuronal migration and neuronal process formation--and lead to the morphological deficits observed in the cretinous brain.

Figure 1. Developmental Fate of the maturing Granule Neuron in the Cerebellum

EGL, external granule layer; ML, molecular layer, IGL, internal granule layer.

Figure 2. Effects of rT₃ on microfilament organization in astrocytes

Astrocytes were grown on p-lysine coated coverslips for 48 h in DMEM containing 10% calf serum and antibiotics. Twenty-four hours before staining, growth medium was replaced with serum-free DMEM containing 1 mg/ml BSA ± 10 nM rT₃. After 24 hrs, coverslips were then washed, fixed with 4% paraformylaldehyde and the actin cytoskeleton visualized with alexafluor⁴⁸⁸-phallacidin as described in ref (41).