DENVER, R.J.: Transcriptional Regulatory Networks Induced by Thyroid Hormone During Metamorphosis of the Amphibian Central Nervous System
Thyroid hormone (T3) induces multiple molecular, biochemical and morphological changes in the tadpole CNS. These changes prepare the animal for the transition from larval to adult life. At the cellular level, T3-induces cell proliferation, death, migration, processelaboration and differentiation. Towards understanding the molecular basis for T3 action on the tadpole brain we isolated several genes that are directly regulated by T3 in Xenopus laevis. Ongoing sequence analysis places these genes into 6 general categories: 1) transcription factors, 2) cellular enzymes, 3) structural proteins, 4) cell cycle control proteins, 5) membrane receptors, 6) secreted signaling molecules. We analyzed the function of several immediate early genes that code for transcription factors. For example, mRNA for the basic transcription element binding protein (BTEB) is strongly induced by T3 in the premetamorphic tadpole brain. Brain BTEB mRNA level rises during metamorphosis and this rise depends on T3. BTEB mRNA expression in the adult brain is low and generally independent of T3. The gene is most highly expressed in the subventricular zone of the telencephalon, regions of the diencephalon and deep cellular layers of the tadpole tectum. We showed that Xenopus BTEB, like mammalian BTEB, binds to GC rich sequences and activates transcription from promoters containing multiple GC boxes. BTEB overexpression and misexpression studies in frogs and rodents suggest a role for this protein in neurite outgrowth and branching. This and other T3-inducible transcription factors likely play critical roles in the signal transduction pathways leading to the diverse changes in the tadpole CNS during metamorphosis. (supported by NSF grant IBN9724080)
