Vps34/PIK3C3 deletion in thyroid impairs thyroid hormonogenesis and autophagic flux
| Autor: | Tongsong Wang, Xiao Hui Liao, Catherine Spourquet, Aurélie Strickaert, Benoit Bilanges, Christophe E. Pierreux, Samuel Refetoff, Carine Maenhaut, Ophélie Delcorte, Virginie Janssens, Bart Vanhaesebroeck, Pierre J. Courtoy, Héloïse P. Gaide Chevronnay, Giuseppina Grieco |
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| Přispěvatelé: | UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/CELL - Biologie cellulaire |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
endocrine system Chemistry Endosome medicine.medical_treatment Thyroid Organification Apical membrane Cell biology 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis medicine Thyroglobulin Homeostasis Tissue homeostasis 030304 developmental biology Hormone |
| Zdroj: | bioRxiv.org, p. [1-38] (2020) |
| Popis: | BACKGROUNDThe production of thyroid hormones (T3, T4) depends on thyroid organization in follicles, lined by a monolayer of thyrocytes with strict apico-basal polarity. Polarization supports vectorial transport of thyroglobulin for storage into, and recapture from, the colloid. It also allows selective addressing of channels, transporters, pumps and enzymes to their appropriate basolateral (NIS and Na+/K+-ATPase) or apical membrane domain (pendrin, anoctamin, DUOX2, DUOXA2 and TPO). How these actors of T3/T4synthesis reach their final destination remains poorly understood. Vps34/PIK3C3 is now recognized as a main component in the general control of vesicular trafficking and of cell homeostasis via autophagy. We recently reported that conditional Vps34 inactivation in kidney proximal tubular cells by Pax8-driven excision prevents normal addressing of apical membrane proteins and causes abortive macroautophagy.METHODSVps34 was inactivated using a Pax8-driven Cre recombinase system. The impact of Vps34 inactivation in thyrocytes was analyzed by histological, immunolocalization and mRNA expression profiling. Thyroid hormone synthesis was assayed by125I injection and by serum plasma analysis.RESULTSVps34cKOmice were born at the expected Mendelian ratio and showed normal growth until postnatal day 14, then stopped growing and died at around 1 month of age. We therefore analyzed thyroid Vps34cKObefore postnatal day 14. We found that loss of Vps34 in thyrocytes causes: (i) disorganization of thyroid parenchyma with abnormal thyrocyte and follicular shape and reduced PAS+colloidal spaces; (ii) impaired125I organification at comparable uptake and frequent occurrence of follicles with luminal thyroglobulin but non-detectable T4-bearing thyroglobulin; (iii) severe non-compensated hypothyroidism with extremely low T4levels (CONCLUSIONSWe conclude that Vps34 is crucial for thyroid hormonogenesis, at least by controlling delivery of apical actors responsible for biogenesis of thyroid hormones on Tg as well as defective proteolytic T3/T4excision in lysosomes. |
| Databáze: | OpenAIRE |
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