ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study used single-cell RNA sequencing to analyze mouse and human thyroid tissue. It discovered two distinct subtypes of thyrocytes, termed thyroid follicular cell (TFC) 1 and TFC2. These subtypes were characterized by varying levels of metabolic activity and Notch signaling: TFC1 cells exhibit higher metabolic activity and Notch signaling compared to the more quiescent TFC2 cells.

Notch signaling is a crucial pathway involved in cell fate determination, and its role in thyroid function was explored using mouse models. By a combination of genetic and pharmacological approaches to disrupt Notch signaling specifically in thyrocytes, mice with targeted deletion of Notch1 and Notch2 in thyrocytes, or treated with Notch pathway-blocking antibodies, developed decreased serum thyroid hormones (TH) and increased TSH levels, and significant dysregulation of whole-body thermoregulation. Further investigation showed that Notch inhibition disturbs a thyrocyte-specific transcriptional program, and induces thyrocyte defects due to decreased mitochondrial activity and reactive oxygen species (ROS) production, which are necessary for TH production. These thyrocyte/mitochondrial defects explained the hypothyroidism observed in the Notch-inhibited mice.

Finally, the authors studied a cohort of 72 children with Alagille syndrome - a disorder caused by mutations in Notch pathway components (JAG1 or NOTCH2). Five patients (7%) were diagnosed with hypothyroidism, representing a 70-fold increase relative to the 0.1% estimated prevalence of pediatric hypothyroidism, confirming a connection between the findings in mice and thyroid dysfunction observed in Alagille syndrome [1].

In September 2023 Wu FY et al. and in March 2024 Zhang HY et al. reported pathogenic variants in MAML2 and MAMLD1, and in CNTN6, respectively, in patients with congenital hypothyroidism due to dyshormonogenesis [2,3]. Pathogenic variants in MAML2 and MALD1, as well as in CNTN6 downregulated Notch signaling, stressing the importance of the findings and new insights about Notch signaling in thyrocytes by Monteiro et al.

References: 1. de Filippis T, Marelli F, Nebbia G, Porazzi P, Corbetta S, Fugazzola L, Gastaldi R, Vigone MC, Biffanti R, Frizziero D, Mandarà L, Prontera P, Salerno M, Maghnie M, Tiso N, Radetti G, Weber G, Persani L. JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects. J Clin Endocrinol Metab. 2016 Mar;101(3):861-70. doi: 10.1210/jc.2015-3403. Epub 2016 Jan 13. PMID: 267601752. Zhang HY, Wu FY, Zhang CX, Wu CY, Cui RJ, Liu XY, Yang L, Zhang Y, Sun F, Cheng F, Yang RM, Song HD, Zhao SX. Contactin 6, A Novel Causative Gene for Congenital Hypothyroidism, Mediates Thyroid Hormone Biosynthesis Through Notch Signaling. Thyroid. 2024 Mar;34(3):324-335. doi: 10.1089/thy.2023.0594. Epub 2024 Feb 12. PMID: 381836243. Wu FY, Yang RM, Zhang HY, Zhan M, Tu PH, Fang Y, Zhang CX, Song SY, Dong M, Cui RJ, Liu XY, Yang L, Yan CY, Sun F, Zhang RJ, Wang Z, Liang J, Song HD, Cheng F, Zhao SX. Pathogenic variations in MAML2 and MAMLD1 contribute to congenital hypothyroidism due to dyshormonogenesis by regulating the Notch signalling pathway. J Med Genet. 2023 Sep;60(9):874-884. doi: 10.1136/jmg-2022-108866. Epub 2023 Mar 10. PMID: 36898841