The molecular basis of thyroid hormone-dependent central nervous system remodeling during amphibian metamorphosis

Tadpole metamorphosis involves a coordinated series of changes in virtually every tissue of the body. This developmental process is induced by the single morphogen, thyroid hormone (TH). The amphibian central nervous system (CNS) is a primary target for TH, and it undergoes dramatic morphological and cytoarchitectural changes in response to the hormone. TH acts by regulating gene expression and its actions in metamorphosis are thought to result from its ability to induce tissue-specific genetic programs. Receptors for TH are ligand-dependent transcription factors whose mRNA expression is upregulated by TH during metamorphosis (receptor autoinduction). Studies on the tadpole CNS have identified four general classes of early TH response genes. These genes code for: (1) transcription factors, that are likely to be required for the expression of downstream genes (i.e. secondary response genes), (2) cellular enzymes, which carry out hormone conversions, energy transformations and may possibly mediate extranuclear effects of TH on neural cells, (3) cytoskeletal elements required for axonal development, and (4) secreted signaling molecules that control the production of TH. Recent studies suggest a critical, evolutionarily conserved role for the TH-induced transcription factor genes in controling neural cell proliferation and differentiation.