Anton Jetten, Ph.D.
Immunity, Inflammation, and Disease Laboratory / Cell Biology Group
D264 Rall Building
111 T W Alexander Dr
Research Triangle Park, NC 27709
Action and functions of retinoic acid-related orphan receptors (RORs)
Retinoic acid-related orphan receptors (RORs) play a critical role in embryonic development as well as in several other physiological processes. RORA and RORC are essential for normal thymopoiesis and Th17 cell differentiation and regulate both innate and adaptive immune responses. RORC-deficient mice exhibited a greatly reduced susceptibility to various autoimmune diseases and allergen-induced lung inflammation. RORC is also essential for lymph node development, while RORA regulates cerebellar development and bone formation. Moreover, RORA and RORC play an important role in the regulation of various metabolic pathways and energy homeostasis. Deficiency in RORA greatly decreases the susceptibility to age- and diet-induced obesity and the development of hepatosteatosis, adipose tissue-associated inflammation, and insulin resistance. RORC-deficient mice also exhibit a greater glucose tolerance. The RORs nuclear receptors function as ligand dependent transcription factors and therefore may provide a novel therapeutic target in the management of obesity and associated metabolic diseases as well as several autoimmune diseases. Our objective is to obtain greater insights in the mechanisms by which these proteins regulate these physiological processes and understand their roles in these diseases.
Physiological functions of GLI-similar (GLIS) transcription factors and roles in disease
The GLIS1-3 proteins constitute a subfamily of Krüppel-like zinc finger transcription factors identified by the Jetten laboratory. These proteins play a critical role in a number of physiological functions and have been implicated in a variety of pathologies. Deficiency in GLIS3 gene in mice and humans leads to the development of neonatal diabetes, hypothyroidism, congenital glaucoma, hepatic fibrosis, polycystic kidneys, osteopenia, as well as developmental delay and facial dysmorphism. Moreover, single nucleotide polymorphisms in GLIS3 have been associated with an increased risk of type 1 and 2 diabetes. GLIS3 plays a critical role in the generation of pancreatic β-cell and in the regulation of insulin gene expression. These findings indicate that GLIS3 might be a therapeutic target for diabetes. Loss of GLIS2 expression leads to nephronophthisis, the most frequent genetic cause of end-stage renal disease among young adults. It is characterized by the development of renal fibrosis, inflammation, tubular atrophy, and ultimately renal failure. The induction of renal fibrosis in GLIS2 deficiency involves epithelial-mesenchymal transition (EMT) of tubule epithelial cells. Our goal is to study the molecular mechanism by which these proteins regulate gene transcription and understand their roles in disease.
Dr. Anton Jetten received his Ph.D in Microbiology from the University Nijmegen, The Netherlands. Following postdoctoral fellowships at the Massachusetts Institute of Technology and the Roche Institute of Molecular Biology, Dr. Jetten joined the NCI in 1980 and the NIEHS in 1982 as principal investigator. He is Deputy Chief of the Immunity, Inflammation, and Disease Laboratory. His research has been focusing on the study of the mechanism of action and the physiological functions of the retinoic acid-related orphan receptors (RORs) and GLI-similar (GLIS) transcription factor subfamilies as well as their roles in disease, particularly lung inflammation, autoimmune disease, obesity and diabetes. Dr. Jetten has published over 260 papers, to date, in scientific journals.
Takeda Y, Kang HS, Freudenberg J, DeGraff LM, Jothi R, Jetten AM. Retinoic acid-related orphan receptor γ (RORγ): a novel participant in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. PLoS Genet. 2014;10(5):e1004331.
Kang HS, Chen LY, Lichti-Kaiser K, Liao G, Gerrish K, Bortner CD, Yao HH, Eddy EM, Jetten AM. Transcription Factor GLIS3: A New and Critical Regulator of Postnatal Stages of Mouse Spermatogenesis. Stem Cells. 2016;34(11):2772-2783.
Dooley J, Tian L, Schonefeldt S, Delghingaro-Augusto V, Garcia-Perez JE, Pasciuto E, Di Marino D, Carr EJ, Oskolkov N, Lyssenko V, Franckaert D, Lagou V, Overbergh L, Vandenbussche J, Allemeersch J, Chabot-Roy G, Dahlstrom JE, Laybutt DR, Petrovsky N, Socha L, Gevaert K, Jetten AM, Lambrechts D, Linterman MA, Goodnow CC, Nolan CJ, Lesage S, Schlenner SM, Liston A. Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes. Nat Genet. 2016;48(5):519-27.
Kang HS, Kumar D, Liao G, Lichti-Kaiser K, Gerrish K, Liao XH, Refetoff S, Jothi R, Jetten AM. GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation. J Clin Invest. 2017;127(12):4326-4337.
Jeon K, Kumar D, Conway AE, Park K, Jothi R, Jetten AM. GLIS3 Transcriptionally Activates WNT Genes to Promote Differentiation of Human Embryonic Stem Cells into Posterior Neural Progenitors. Stem Cells. 2019;37(2):202-215.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on August 21st, 2019