The long-term objective of this work is to elucidate the molecular mechanisms which bring about cell-type-specific gene expression in the developing nervous system. This will be accomplished by analysis of the mechanism by which thyroxine induces the development of a specific population of retinal ganglion cell axons. The information necessary to guide neuronal development is encoded in the genetic apparatus. The regulation of gene expression is in many situations controlled by specific molecules which interact with particular sequences of DNA. Hormones are one such type of regulatory molecule, and for thyroid hormones, interaction with chromatin-associated receptor molecule is the first step in the regulation of specific gene expression. Thyroid hormones are of critical importance for normal development of the vertebrate nervous system. For mammals, chronic thyroxine deficiency results in loss of neurons, poor coordination, and in humans, mental retardation. For amphibians, if thyroxine is absent development is arrested permanently at a tadpole stage. Injection of thyroxine to the eye of metamorphically-arrested tadpoles induces the development of a specific axonal projection to a unique target in the brain. The effect is local rather than systemic; thyroxine appears to produce a new type of ganglion cell, one which is intrinsically """"""""programmed"""""""" or which reads environmental signals in a new way, enabling its axon to find a different target. The clear temporal distinction between periods of thyroxine- independent and thyroxine-dependent retinal development will allow the isolation of thyroxine-regulated genes by differential screening of a cDNA library made from thyroxine-stimulated poly A+ retinal RNA. Existing data, in conjunction with new information from experiments focused on the development of thyroxine-regulated axons, will allow isolation of thyroxine-regulated retinal genes whose expression can be related directly to axonal development. Thus this experimental system offers the possibility of analyzing a fundamental issue in developmental neurobiology-- the control of axonal projection specificity-- in a system where an inducer of axonal outgrowth, thyroxine, has been defined and can be analyzed at both cellular and molecular levels.
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