PUBLICATION
In vivo functional consequences of human THRA variants expressed in the zebrafish
- Authors
- Marelli, F., Carra, S., Rurale, G., Cotelli, F., Persani, L.
- ID
- ZDB-PUB-161105-20
- Date
- 2017
- Source
- Thyroid : official journal of the American Thyroid Association 27(2): 279-291 (Journal)
- Registered Authors
- Cotelli, Franco
- Keywords
- none
- MeSH Terms
-
- Anemia/genetics
- Animals
- Animals, Genetically Modified
- Brain Edema/genetics
- Congenital Hypothyroidism/genetics*
- Congenital Hypothyroidism/metabolism
- Craniofacial Abnormalities/genetics
- Disease Models, Animal*
- Edema, Cardiac/genetics
- Embryo, Nonmammalian/metabolism
- Gene Expression Regulation, Developmental
- Genetic Variation
- Humans
- Motor Neuron Disease/congenital
- Motor Neuron Disease/genetics
- Thyroid Hormone Receptors alpha/genetics*
- Thyrotropin/metabolism
- Thyrotropin, beta Subunit/metabolism
- Thyrotropin-Releasing Hormone/metabolism
- Thyroxine/metabolism
- Triiodothyronine/metabolism
- Zebrafish*
- PubMed
- 27809680 Full text @ Thyroid
Citation
Marelli, F., Carra, S., Rurale, G., Cotelli, F., Persani, L. (2017) In vivo functional consequences of human THRA variants expressed in the zebrafish. Thyroid : official journal of the American Thyroid Association. 27(2):279-291.
Abstract
Heterozygous mutations in the thyroid hormone receptor alpha (THRA) gene cause Resistance to Thyroid Hormone alpha (RTHα), a disease characterized by variable manifestations reminiscent of untreated congenital hypothyroidism but a raised T3/T4 ratio and normal TSH levels. We recently described that zebrafish embryos expressing a dominant negative (DN) form of thraa recapitulate the key features of RTHα, and that zebrafish and human receptors are functionally interchangeable. In this study we expressed several human TRα variants in zebrafish embryos and analyzed the resulting phenotypes. All hTRα-injected embryos show variable defects including cerebral and cardiac edema likely caused by an aberrant looping during heart development, anemia and an incomplete formation of the vascular network. Moreover, the hTRα-injected embryos present severe defects of motorneurons and craniofacial development thus affecting their autonomous feeding and swimming behaviors. Surprisingly, expression of all hTRα mutants had no detectable effect on TSHβ and TRH transcripts, indicating that their DN action is limited on the TRβ2 targets at the hypothalamic/pituitary level in vivo. As previously described in vitro, treatment with high T3 doses can efficiently revert the observed defects only in embryos injected with missense hTRα variants. In conclusion, injection of human THRA variants in the zebrafish embryos cause tissue specific defects recapitulating most of the RTHα clinical and biochemical manifestations. The described manipulation of zebrafish embryos represents a novel in vivo model to screen the functional consequences of THRA variants and the rescue potential of new therapeutic compounds.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping