Differential thyroid hormone sensitivity of fast cycling progenitors in the neurogenic niches of tadpoles and juvenile frogs

Abstract

Adult neurogenesis occurs in neural stem cell (NSC) niches where slow cycling stem cells give rise to faster cycling progenitors. In the adult mouse NSC niche thyroid hormone, T3, and its receptor TRα act as a neurogenic switch promoting progenitor cell cycle completion and neuronal differentiation. Little is known about whether and how T3 controls proliferation of differentially cycling cells during xenopus neurogenesis. To address this question, we first used Sox3 as a marker of stem cell and progenitor populations and then applied pulse-chase EdU/IdU incorporation experiments to identify Sox3-expressing slow cycling (NSC) and fast cycling progenitor cells. We focused on the lateral ventricle of Xenopus laevis and two distinct stages of development: late embryonic development (pre-metamorphic) and juvenile frogs (post-metamorphic). These stages were selected for their relatively stable thyroid hormone availability, either side of the major dynamic phase represented by metamorphosis. TRα expression was found in both pre and post-metamorphic neurogenic regions. However, exogenous T3 treatment only increased proliferation of the fast cycling Sox3+ cell population in post-metamorphic juveniles, having no detectable effect on proliferation in pre-metamorphic tadpoles. We hypothesised that the resistance of proliferative cells to exogenous T3 in pre-metamorphic tadpoles could be related to T3 inactivation by the inactivating Deiodinase 3 enzyme. Expression of dio3 was widespread in the tadpole neurogenic niche, but not in the juvenile neurogenic niche. Use of a T3-reporter transgenic line showed that in juveniles, T3 had a direct transcriptional effect on rapid cycling progenitors. Thus, the fast cycling progenitor cells in the neurogenic niche of tadpoles and juvenile frogs respond differentially to T3 as a function of developmental stage.