Regulation of cerebellar neuronal migration and neurite outgrowth by thyroxine and 3,3',5'-triiodothyronine
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Medicine, Division of Endocrinology and Metabolism; Brudnick Neuropsychiatric Research Institute; Department of Physiology
Life Sciences | Medicine and Health Sciences
The timing of granule cell migration in the developing cerebellum is regulated by thyroid hormone. Granule cell migration depends on the recognition of extracellular neuronal guidance molecule(s), such as laminin, and this, in turn, requires cell surface adhesion molecules (integrins) that are anchored on the cell membrane by the actin cytoskeleton. While many of the actions of thyroid hormone, specifically 3,5,3'-triiodothyronine (T3), are mediated by regulated gene expression, both thyroxine (T4) and 3,3',5'-triiodothyronine (rT3) also exert direct, positive control of the quantity of polymerized actin in cultured astrocytes without affecting gene expression. T4-dependent actin polymerization has been shown to (i) participate in the immobilization of laminin to the cell surface, (ii) help deposit laminin in the molecular layer of the developing cerebellum, and (iii) anchor integrin(s) that recognize laminin present in the extracellular matrix. In this study, we show that both T4 and rT3, but not T3, directly regulate the F-actin content of elongating neurites of cerebellar neurons. T4 and rT3 also promoted extensive granule cell migration from cerebellar explants, as well as, dense cell clustering and extensive neuronal process formation when granule cells were grown on a laminin-coated surface. Both granule cell migration and neuronal process outgrowth were markedly attenuated by the addition of integrin-blocking antibodies or binding peptides, by the absence of thyroid hormone or the presence of T3. These data suggest that the T4-dependent actin polymerization in developing neurons is necessary for these migrating cells to recognize the laminin guidance molecule, thereby providing a novel molecular mechanism for the profound influence of thyroid hormone on brain development that is independent of regulated gene expression.
DOI of Published Version
Brain Res Dev Brain Res. 2005 Jan 1;154(1):121-35. Link to article on publisher's site
Brain research. Developmental brain research
Farwell, Alan P.; Dubord-Tomasetti, Susan A.; Pietrzykowski, Andrzej Z.; Stachelek, Stanley J.; and Leonard, Jack L., "Regulation of cerebellar neuronal migration and neurite outgrowth by thyroxine and 3,3',5'-triiodothyronine" (2004). GSBS Student Publications. 276.