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 β 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.
Laboratory of Comparative Endocrinology, Division Animal Physiology and Neurobiology, Biology Department, KU Leuven, B-3000 Leuven, Belgium.
Stitipragyan
S
Bhumika
Laboratory of Neural Circuit Development and Regeneration, Division Animal Physiology and Neurobiology, Biology Department, KU Leuven, B-3000 Leuven, Belgium.
Kim
K
Lemmens
Laboratory of Comparative Endocrinology, Division Animal Physiology and Neurobiology, Biology Department, KU Leuven, B-3000 Leuven, Belgium.
Pieter
P
Vancamp
Laboratory of Neural Circuit Development and Regeneration, Division Animal Physiology and Neurobiology, Biology Department, KU Leuven, B-3000 Leuven, Belgium.
Lieve
L
Moons
Laboratory of Comparative Endocrinology, Division Animal Physiology and Neurobiology, Biology Department, KU Leuven, B-3000 Leuven, Belgium. Electronic address: veerle.darras@bio.kuleuven.be.
Veerle M
VM
Darras
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000627:therapeutic use; D006727:Hormone Antagonists / Q000494:pharmacology; D007480:Iopanoic Acid / Q000627:therapeutic use; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000503:physiopathology*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013477:Superior Colliculi / Q000187:drug effects / Q000502:physiology*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
D006573:Heterocyclic Compounds, 1-Ring; D006727:Hormone Antagonists; D009419:Nerve Tissue Proteins; D013963:Thyroid Hormones; C008160:iophenoxic acid; D014446:Tyrosine 3-Monooxygenase; D007480:Iopanoic Acid; C013411:biocytin; D008239:Lysine
Inflammation; Neuroregeneration; Optic nerve; Thyroid hormone; Zebrafish