Understanding of the in vivo molecular actions of the TRalpha1 mutant has been limited since the initial identification of patients with THRA mutations. However, by using Thra1PV/+ mice we have elucidated how TRalpha1 mutants act to cause pathological manifestations in patients, such as erythroid and intestine disorders. We found that TRalpha1PV acts to suppress the clonogenic potential of progenitors in the erythrocytic lineage in bone marrow, leading to a reduction of mature erythrocytes. Further, we found that a key driver in the erythropoiesis, the Gata-1 gene, is a T3-directly regulated gene. TRalpha1PV impairs erythropoiesis, at least in part, via repression of the Gata-1 gene expression and its downstream regulated genes, causing anemia. We also demonstrated that adult Thra1PV/+ mice exhibit constipation as do RTHalpha patients. Further, we detected shorter villi and reduced stem-cell proliferation in the intestine crypts of Thra1PV/+ mice. These findings further demonstrated that we can use the Thra1PV/+ mouse to analyze in depth the pathogenetic actions of TRalpha1 mutants in human RTHalpha. Recently we have generated novel RTHalpha models in zebrafish to facilitate the study of the pathogenetic actions of TRalpha1 mutants in early development. We cannot use the Thra1PV/+ mouse to study TRalpha1 mutants in early development because of the insurmountable difficulty obtaining sufficient mutant embryos. Zebrafish have been increasingly used as models for human diseases owing to their high fecundity, rapid external embryonic development, and the easy visualization of transparent embryos. The zebrafish have two duplicated thra genes, thraa and thrab. Their encoded receptors show a high extent of amino acid sequence homology in the functional DNA and hormone binding domains with those of human and mouse TRalpha1 (90-95%). Using CRISPR/Cas9-mediated targeted mutagenesis, we created germline transmittable mutant fish. The stable expression of thra mutants from embryos to adulthood facilitated the study of molecular actions of TRalpha1 mutants during embryonic development as well as post-embryonic development. Two mutant fish lines expressing a mutation in the thraa gene (thraa 8-bp insertion mutant gene, encoding ThraaLeu405Glufs*6 mutant receptor) or the thrab gene (thrab 1-bp insertion mutant gene, encoding ThrabGlu394* mutant receptor) were obtained. These C-terminal truncation dominant negative mutant receptors were similar to those identified in patients. Adult and juvenile ThrabGlu394* mutants exhibited severe growth retardation, but adult ThraaLeu405Glufs*6 mutants had only very mild growth impairment. Expression of growth hormone in the pituitary and insulin-like growth factor 1 in muscle was markedly suppressed in ThrabGlu394* mutants. Decreased mRNA and protein levels of T3-regulated keratin genes and inhibited keratinocyte proliferation resulted in epidermal hypoplasia in adult and juvenile ThrabGlu394* mutants, but not ThraaLeu405Glufs*6 mutant fish. RNA-seq analysis showed that ThrabGlu394* mutation had global impact on the functions of the adult pituitary. However, neither morphological defects nor any changes in the expression of gh1 and keratin genes were observed in the embryos and early larvae. Thus, mutations of either the thraa or thrab gene did not affect initiation of embryogenesis. Rather, the mutation of the thrab gene, but not the thraa gene, is detrimental in post-larva growth and skin development. These differential effects suggested that the thra duplicated genes are essential to control temporal coordination in post-larva growth and development in a tissue-specific manner. Our studies uncovered novel functions of the duplicated thra genes in zebrafish in development. These mutant zebrafish could be used as models for further analysis of in vivo actions of TRalpha1 mutants during development and for large-scale screening of therapeutics for RTHalpha.