PUBLICATION
Tsh induces Agrp1 neuron proliferation in Oatp1c1 deficient zebrafish
- Authors
- Wasserman-Bartov, T., Admati, I., Lebenthal-Loinger, I., Sharabany, J., Lerer-Goldshtein, T., Appelbaum, L.
- ID
- ZDB-PUB-220924-46
- Date
- 2022
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 42(44): 8214-8224 (Journal)
- Registered Authors
- Admati, Inbal, Appelbaum, Lior
- Keywords
- none
- MeSH Terms
-
- Adolescent
- Animals
- Anions
- Cell Proliferation
- Female
- Humans
- Intracellular Signaling Peptides and Proteins*/genetics
- Intracellular Signaling Peptides and Proteins*/metabolism
- Larva/metabolism
- Male
- Monocarboxylic Acid Transporters*/genetics
- Monocarboxylic Acid Transporters*/metabolism
- Neurons/metabolism
- Organic Anion Transporters*/genetics
- Organic Anion Transporters*/metabolism
- Symporters*/metabolism
- Thyroid Hormones
- Thyrotropin/metabolism
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 36150888 Full text @ J. Neurosci.
Citation
Wasserman-Bartov, T., Admati, I., Lebenthal-Loinger, I., Sharabany, J., Lerer-Goldshtein, T., Appelbaum, L. (2022) Tsh induces Agrp1 neuron proliferation in Oatp1c1 deficient zebrafish. The Journal of neuroscience : the official journal of the Society for Neuroscience. 42(44):8214-8224.
Abstract
Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), regulate growth, metabolism, and neurodevelopment. THs secretion is controlled by the pituitary thyroid-stimulating hormone (TSH) and the hypothalamic-pituitary-thyroid (HPT) axis. The organic anion-transporting polypeptide 1C1 (OATP1C1/Slco1c1) and the monocarboxylate transporter 8 (MCT8/SLC16A2) actively transport THs, which bind to their nuclear receptors and induce gene expression. A mutation in OATP1C1 is associated with brain hypometabolism, gradual neurodegeneration, and impaired cognitive and motor functioning in adolescent patients. In order to understand the role of Oatp1c1 and the mechanisms of the disease, we profiled the transcriptome of oatp1c1 mutant (oatp1c1-/-) and mct8-/-xoatp1c1-/- adult male and female zebrafish brains. Among dozens of differentially expressed genes, agouti-related neuropeptide 1 (agrp1) expression increased in oatp1c1-/- adult brains. Imaging in the hypothalamus revealed enhanced proliferation of Agrp1 neurons in oatp1c1-/- larvae and adults, and increased food consumption in oatp1c1-/- larvae. Similarly, feeding and the number of Agrp1 neurons increased in thyroid gland-ablated zebrafish. Pharmacological treatments showed that the T3 analog 3,3',5-tri-iodothyroacetic acid (TRIAC), but not T4, normalized the number of Agrp1 neurons in oatp1c1-/- zebrafish. Since the HPT axis is hyperactive in the oatp1c1-/- brain, we used the CRISPR-Cas9 system to knockdown (KD) tsh in oatp1c1-/- larvae, and inducibly enhanced the HPT axis in wild-type (WT) larvae. These manipulations showed that Tsh promotes proliferation of Agrp1 neurons and increases food consumption in zebrafish. The results revealed upregulation of both the HPT axis-Agrp1 circuitry and feeding in a zebrafish model for OATP1C1-deficiency.Significant StatementMutation in the TH transporter OATP1C1 is associated with cognitive and motor functioning disturbances in humans. Here, we used an oatp1c1-/- zebrafish to understand the role of Oatp1c1, and the characteristics of OATP1C1-deficiency. Transcriptome profiling identified upregulation of agrp1 expression in the oatp1c1-/- brain. The oatp1c1-/- larvae showed increased tsh levels, proliferation of Agrp1 neurons and food consumption. Genetic manipulations of the HPT axis showed that Tsh increases the number of Agrp1 neurons and food consumption. The TH analog TRIAC normalizes the number of Agrp1 neurons and may have potential for the treatment of Oatp1c1-deficiency. The findings demonstrate a functional interaction between the thyroid and feeding systems in the brain of zebrafish, and suggest a neuroendocrinological mechanism for OATP1C1-deficiency.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping