The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine.
Thyroid hormones control various aspects of gut development and homeostasis. The best-known example is in gastrointestinal tract remodeling during amphibian metamorphosis. It is well documented that these hormones act via the TR nuclear receptors, which are hormone-modulated transcription factors. Several studies have shown that thyroid hormones regulate the expression of several genes in the Notch signaling pathway, indicating a possible means by which they participate in the control of gut physiology. However, the mechanisms and biological significance of this control have remained unexplored. Using multiple in vivo and in vitro approaches, we show that thyroid hormones positively regulate Notch activity through the TRα1 receptor. From a molecular point of view, TRα1 indirectly controls Notch1, Dll1, Dll4 and Hes1 expression but acts as a direct transcriptional regulator of the Jag1 gene by binding to a responsive element in the Jag1 promoter. Our findings show that the TRα1 nuclear receptor plays a key role in intestinal crypt progenitor/stem cell biology by controlling the Notch pathway and hence the balance between cell proliferation and cell differentiation.
Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, 16 Rue Raphael Dubois, Villeurbanne 69622, France.
Maria
M
Sirakov
Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, 16 Rue Raphael Dubois, Villeurbanne 69622, France.
Amina
A
Boussouar
Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, 16 Rue Raphael Dubois, Villeurbanne 69622, France.
Elsa
E
Kress
Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, 16 Rue Raphael Dubois, Villeurbanne 69622, France.
Carla
C
Frau
Laboratoire de Biologie Moléculaire de la cellule, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, Lyon 69007, France.
Imtiaz Nisar
IN
Lone
Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, 16 Rue Raphael Dubois, Villeurbanne 69622, France.
Julien
J
Nadjar
Laboratoire de Biologie Moléculaire de la cellule, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, Lyon 69007, France.
Dimitar
D
Angelov
Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, 16 Rue Raphael Dubois, Villeurbanne 69622, France michelina.plateroti@univ-lyon1.fr.
Michelina
M
Plateroti
D000818:Animals; D015153:Blotting, Western; D019070:Cell Lineage / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000502:physiology; D006980:Hyperthyroidism / Q000378:metabolism*; D007150:Immunohistochemistry; D007422:Intestines / Q000166:cytology* / Q000502:physiology; D051379:Mice; D018613:Microscopy, Confocal; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*
C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D037021:Thyroid Hormone Receptors alpha
Intestinal epithelium; Mouse; Notch pathway; Thra; Thyroid hormone nuclear receptor; Thyroid hormones