Dissecting the role of regulators of thyroid hormone availability in early brain development: Merits and potential of the chicken embryo model.

Thyroid hormones (THs) are important mediators of vertebrate central nervous system (CNS) development, thereby regulating the expression of a wide variety of genes by binding to nuclear TH receptors. TH transporters and deiodinases are both needed to ensure appropriate intracellular TH availability, but the precise function of each of these regulators and their coaction during brain development is only partially understood. Rodent knockout models already provided some crucial insights, but their in utero development severely hampers research regarding the role of TH regulators during early embryonic stages. The establishment of novel gain- and loss-of-function techniques has boosted the position of externally developing non-mammalian vertebrates as research models in developmental endocrinology. Here, we elaborate on the chicken as a model organism to elucidate the function of TH regulators during embryonic CNS development. The fast-developing, relatively big and accessible embryo allows easy experimental manipulation, especially at early stages of brain development. Recent data on the characterisation and spatiotemporal expression pattern of different TH regulators in embryonic chicken CNS have provided the necessary background to dissect the function of each of them in more detail. We highlight some recent advances and important strategies to investigate the role of TH transporters and deiodinases in various CNS structures like the brain barriers, the cerebellum, the retina and the hypothalamus. Exploiting the advantages of this non-classical model can greatly contribute to complete our understanding of the regulation of TH bioavailability throughout embryonic CNS development.

Decreased thyroid hormone signaling accelerates the reinnervation of the optic tectum following optic nerve crush in adult zebrafish.

The regenerative capacity of the adult mammalian central nervous system (CNS) is poor and finding ways to stimulate long distance axonal regeneration in humans remains a challenge for neuroscientists. Thyroid hormones, well known for their key function in CNS development and maturation, more recently also emerged as molecules influencing regeneration. While several studies investigated their influence on peripheral nerve regeneration, in vivo studies on their role in adult CNS regeneration remain scarce. We therefore investigated the effect of lowering T3 signaling on the regeneration of the optic nerve (ON) following crush in zebrafish, a species where full recovery occurs spontaneously. Adult zebrafish were exposed to iopanoic acid (IOP), which lowered intracellular 3,5,3'-triiodothyronine (T3) availability, or to the thyroid hormone receptor ß antagonist methylsulfonylnitrobenzoate (C1). Both treatments accelerated optic tectum (OT) reinnervation. At 7days post injury (7dpi) there was a clear increase in the biocytin labeled area in the OT following anterograde tracing as well as an increased immunostaining of Gap43, a protein expressed in outgrowing axons. This effect was attenuated by T3 supplementation to IOP-treated fish. ON crush induced very limited cell death and proliferation at the level of the retina in control, IOP- and C1-treated fish. The treatments also had no effect on the mRNA upregulation of the regeneration markers gap43, tub1a, and socs3b at the level of the retina at 4 and 7dpi. We did, however, find a correlation between the accelerated OT reinnervation and a more rapid resolution of microglia/macrophages in the ON and the OT of IOP-treated fish. Taken together these data indicate that lowering T3 signaling accelerates OT reinnervation following ON crush in zebrafish and that this is accompanied by a more rapid resolution of the inflammatory response.