Small-Molecule Screening in Zebrafish Embryos Identifies Signaling Pathways Regulating Early Thyroid Development
| Autor: | Isabelle Vandernoot, Sabine Costagliola, Nicoletta Giusti, Achim Trubiroha, Pierre Gillotay, Benoit Haerlingen, Robert Opitz |
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| Rok vydání: | 2019 |
| Předmět: |
endocrine system
Embryo Nonmammalian endocrine system diseases Endocrinology Diabetes and Metabolism Thyroid Gland Embryonic Development 030209 endocrinology & metabolism heart thyroid Small Molecule Libraries 03 medical and health sciences 0302 clinical medicine Endocrinology medicine Animals development Zebrafish Organisms Genetically Modified biology cardiovascular Thyroid Embryogenesis congenital hypothyroidism Gene Expression Regulation Developmental Sciences bio-médicales et agricoles zebrafish medicine.disease biology.organism_classification Small molecule High-Throughput Screening Assays Congenital hypothyroidism Cell biology Fibroblast Growth Factors Phenotype medicine.anatomical_structure 030220 oncology & carcinogenesis Bone Morphogenetic Proteins Thyroid Dysgenesis Zebrafish embryo Intercellular Signaling Peptides and Proteins Signal transduction Signal Transduction |
| Zdroj: | Thyroid, 29 (11 |
| ISSN: | 1557-9077 1050-7256 |
| Popis: | Background: Defects in embryonic development of the thyroid gland are a major cause for congenital hypothyroidism in human newborns, but the underlying molecular mechanisms are still poorly understood. Organ development relies on a tightly regulated interplay between extrinsic signaling cues and cell intrinsic factors. At present, however, there is limited knowledge about the specific extrinsic signaling cues that regulate foregut endoderm patterning, thyroid cell specification, and subsequent morphogenetic processes in thyroid development. Methods: To begin to address this problem in a systematic way, we used zebrafish embryos to perform a series of in vivo phenotype-driven chemical genetic screens to identify signaling cues regulating early thyroid development. For this purpose, we treated zebrafish embryos during different developmental periods with a panel of small-molecule compounds known to manipulate the activity of major signaling pathways and scored phenotypic deviations in thyroid, endoderm, and cardiovascular development using whole-mount in situ hybridization and transgenic fluorescent reporter models. Results: Systematic assessment of drugged embryos recovered a range of thyroid phenotypes including expansion, reduction or lack of the early thyroid anlage, defective thyroid budding, as well as hypoplastic, enlarged, or overtly disorganized presentation of the thyroid primordium after budding. Our pharmacological screening identified bone morphogenetic protein and fibroblast growth factor signaling as key factors for thyroid specification and early thyroid organogenesis, highlighted the importance of low Wnt activities during early development for thyroid specification, and implicated drug-induced cardiac and vascular anomalies as likely indirect mechanisms causing various forms of thyroid dysgenesis. Conclusions: By integrating the outcome of our screening efforts with previously available information from other model organisms including Xenopus, chicken, and mouse, we conclude that signaling cues regulating thyroid development appear broadly conserved across vertebrates. We therefore expect that observations made in zebrafish can inform mammalian models of thyroid organogenesis to further our understanding of the molecular mechanisms of congenital thyroid diseases. info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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