NF-κB Essential Modulator (NEMO) Is Critical for Thyroid Function

Abstract

The I-B kinase (IKK) subunit NEMO/IKK␥ (NEMO) is an adapter molecule that is critical for canonical activation of NF-B, a pleiotropic transcription factor controlling immunity, differentiation, cell growth, tumorigenesis, and apoptosis. To explore the functional role of canonical NF-B signaling in thyroid gland differentiation and function, we have generated a murine strain bearing a genetic deletion of the NEMO locus in thyroid. Here we show that thyrocyte-specific NEMO knock-out mice gradually develop hypothyroidism after birth, which leads to reduced body weight and shortened life span. Histological and molecular analysis indicate that absence of NEMO in thyrocytes results in a dramatic loss of the thyroid gland cellularity, associated with down-regulation of thyroid differentiation markers and ongoing apoptosis. Thus, NEMO-dependent signaling is essential for normal thyroid physiology.

Identification of <b><i>Transient Receptor Potential Channel 4-Associated Protein</i></b> as a Novel Candidate Gene Causing Congenital Primary Hypothyroidism

“…These characteristics match very well to those found in Xenopus laevis using MO antisense oligomers exhibiting a hypoplastic thyroid anlage ( Fig. 3) and to those found in NEMOTS-KO thyrocytes undergoing progressive apoptosis after birth [20]. Moreover, patients with hypohydrotic ectodermal dysplasia develop primary hypothyroidism in infancy [21][22][23].…”

“…In fact, NF-kB controls the expression of thyroid proteins, including sodium iodide symporter, TTF 1/NKX2-1, PAX8, TPO, and TG. It was concluded that IKBKG-dependent signaling is essential for thyrocyte survival and maintenance of thyroid marker expression [20,28]. These findings may also reflect the potential role of the complex TRPC4AP/ IKBKG in the pathophysiology of congenital primary thyroid disease with deteriorating postnatal thyroid function.…”

“…4, Ingenuity Pathway Analysis) and seems to be linked to TSH regulation of thyroid function (TSH receptor, TSHR), to govern key enzymes involved in transmembrane iodine transport (SLC26A4/pendrin, SLC5A5/sodium iodide symporter) and intrathyroidal hormone synthesis (Tg, DUOX1/2, TPO) and is related to the transport of thyroxine from blood to cerebrospinal fluid (SLC16A2/ MCT-8). Furthermore, TRPC4AP and IKBKG are interconnected with thyroid transcription factors (NKX 2-1 (thyroid transcription factor 1/TTF1), PAX8, FOXE1, GLIS3, and probably NKX2-5) which chaperone the organogenesis of the thyroid gland [20]. Defects in all of these transcription factors and peptides have been detected in patients with CH due to dysgenesis and dyshormonogenesis [4].…”

“…TRPC4AP is located at 20q11.22, encoded by 19 exons, and represents an ubiquitous scaffold and signaling pro-tein which is associated with the tumor necrosis factor receptor and mediates activation of the transcription factor NF-kB and interacts as an adapter molecule with components of the I-kB kinase subunit NF-kB essential modulator IKBKG (NEMO) [20,[24][25][26]. IKBKG functions as a kinase in numerous cell signaling pathways specifically phosphorylating serine or threonine residues that are followed by a proline residue [27].…”

Unraveling the Mechanistic Complexity of the Glomerulocystic Phenotype in Dicer Conditional KO Mice by 2D Gel Electrophoresis Coupled Mass Spectrometry

“…Right kidney was embedded in paraffin and 4 μm sections were stained with hematoxylin and eosin (Sigma‐Aldrich, Milan, Italy) according to the manufacturer's instructions. The immunoperoxidase and immunofluorescence were performed as already described . For immunoperoxidase and immunofluorescence staining the following primary antibodies were used: rabbit anti‐Cyclin D1 H‐295 (sc 753, Santa Cruz) dilution 1:50; rabbit anti‐c‐Myc (ab 32072, Abcam) dilution 1:100; rabbit anti‐ERK1 (C‐16) (sc 93, Santa Cruz) dilution 1:50; rabbit anti‐phospho P44/42 (Thr202‐T204) (9101S, Cell Signaling) dilution 1:50.…”