scholarly journals IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction

2019 ◽  
Vol 105 (3) ◽  
pp. e70-e84 ◽  
Author(s):  
Sjoerd D Joustra ◽  
Ferdinand Roelfsema ◽  
A S Paul van Trotsenburg ◽  
Harald J Schneider ◽  
Robert P Kosilek ◽  
...  
Keyword(s):  
Immunoglobulin Superfamily ◽  
Pituitary Cells ◽  
Adult Males ◽  
Loss Of Function ◽  
Central Hypothyroidism ◽  
Gh Secretion ◽  
Soft Tissue Thickness ◽  
Median Serum ◽  
Deficient Mice ◽  
Gh Excess

Abstract Context The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. Objective We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. Patients, Design, and Setting We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. Main Outcome Measures We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. Results IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. Conclusions We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.

scholarly journals Spatial and temporal expression of immunoglobulin superfamily member 1 in the rat

2015 ◽  
Vol 226 (3) ◽  
pp. 181-191 ◽  
Author(s):  
Sjoerd D Joustra ◽  
Onno C Meijer ◽  
Charlotte A Heinen ◽  
Isabel M Mol ◽  
El Houari Laghmani ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Pituitary Gland ◽  
Mrna Expression ◽  
Fetal Liver ◽  
Expression Patterns ◽  
Immunoglobulin Superfamily ◽  
Pituitary Hormone ◽  
Loss Of Function ◽  
Central Hypothyroidism ◽  
The Brain

Loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene cause an X-linked syndrome of central hypothyroidism, macroorchidism, variable prolactin and GH deficiency, delayed pubertal testosterone rise, and obesity. To understand the pathophysiology of this syndrome, knowledge on IGSF1's place in normal development is imperative. Therefore, we investigated spatial and temporal protein and mRNA expression of IGSF1 in rats using immunohistochemistry, real-time quantitative PCR (qPCR), and in situ hybridization. We observed high levels of IGSF1 expression in the brain, specifically the embryonic and adult choroid plexus and hypothalamus (principally in glial cells), and in the pituitary gland (PIT1-lineage of GH, TSH, and PRL-producing cells). IGSF1 is also expressed in the embryonic and adult zona glomerulosa of the adrenal gland, islets of Langerhans of the pancreas, and costameres of the heart and skeletal muscle. IGSF1 is highly expressed in fetal liver, but is absent shortly after birth. In the adult testis, IGSF1 is present in Sertoli cells (epithelial stages XIII–VI), and elongating spermatids (stages X–XII). Specificity of protein expression was corroborated with Igsf1 mRNA expression in all tissues. The expression patterns of IGSF1 in the pituitary gland and testis are consistent with the pituitary hormone deficiencies and macroorchidism observed in patients with IGSF1 deficiency. The expression in the brain, adrenal gland, pancreas, liver, and muscle suggest IGSF1's function in endocrine physiology might be more extensive than previously considered.

scholarly journals IGSF1 Does Not Regulate Spermatogenesis or Modify FSH Synthesis in Response to Inhibins or Activins

2021 ◽  
Vol 5 (4) ◽  
Author(s):  
Emilie Brûlé ◽  
Charlotte A Heinen ◽  
Courtney L Smith ◽  
Gauthier Schang ◽  
Yining Li ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Follicle Stimulating Hormone ◽  
Inhibin B ◽  
Immunoglobulin Superfamily ◽  
Type I ◽  
Testis Size ◽  
Loss Of Function ◽  
Central Hypothyroidism ◽  
Sperm Counts ◽  
Stimulation Of

AbstractLoss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as an inhibitor of activin type I receptor (ALK4) activity in pituitary gonadotrope cells. If true, loss of IGSF1 should lead to reduced inhibin B action or disinhibition of activin signaling, thereby increasing FSH synthesis. Here, we show that FSH levels and sperm counts are normal in male Igsf1 knockout mice, although testis size is mildly increased. Sperm parameters are also normal in men with IGSF1 deficiency, although their FSH levels may trend higher and their testes are enlarged. Inhibin B retains the ability to suppress FSH synthesis in pituitaries of Igsf1-knockout mice and IGSF1 does not interact with ALK4 or alter activin A/ALK4 stimulation of FSHβ (Fshb/FSHB) subunit transcription or expression. In light of these results, it is unlikely that macroorchidism in IGSF1 deficiency derives from alterations in spermatogenesis or inhibin/activin regulation of FSH.

scholarly journals CircAgtpbp1 Acts as a Molecular Sponge of miR-543-5p to Regulate the Secretion of GH in Rat Pituitary Cells

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 558
Author(s):  
ZeWen Yu ◽  
WenZhi Ren ◽  
Tian Wang ◽  
WeiDi Zhang ◽  
ChangJiang Wang ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Inhibitory Effect ◽  
Pituitary Cells ◽  
Sequencing Analysis ◽  
Hormone Regulation ◽  
Gh Secretion ◽  
Qrt Pcr ◽  
Rat Pituitary ◽  
Rat Pituitary Cells

CircRNAs have been identified to be expressed differently and stably in numerous species and tissues, but their functions in growth hormone (GH) secretion are still largely unknown. In summary, we have revealed a circRNA-miRNA-mRNA network that may play a biological role in the rat pituitary gland. First, we verified the chromosome location information of circAgtpbp1 according to sequencing analysis. The circAgtpbp1 characteristics were authenticated through PCR, qRT–PCR, treating with RNase and fluorescent in situ hybridization (FISH). Second, we detected the expression pattern of circAgtpbp1 in the rat anterior pituitary by qRT–PCR. We also designed circAgtpbp1 siRNA and constructed overexpression plasmid to evaluate the effect of circAgtpbp1 function on GH secretion by qRT–PCR, ELISA and Western blot. CircAgtpbp1 is a stable, truly circular molecule. We found that circAgtpbp1 interacted with miR-543-5p and can regulate GH secretion in pituitary cells through a circAgtpbp1-miR-543-5p-GH axis. Overall, the evidence generated by our study suggests that circAgtpbp1 can act as a sponge of miR-543-5p to reduce the inhibitory effect of miR-543-5p on Gh1 and further promote GH secretion. These findings expand our existing knowledge on the mechanisms of hormone regulation in the pituitary gland.

scholarly journals Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 357
Author(s):  
Mojca Trstenjak Prebanda ◽  
Petra Matjan-Štefin ◽  
Boris Turk ◽  
Nataša Kopitar-Jerala
Keyword(s):  
Mouse Model ◽  
Redox Homeostasis ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Altered Expression ◽  
Lps Challenge ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
The Brain ◽  
Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

16. Physiological effects of IDH1 loss-of-function on Chondrocyte Differentiation through Hedgehog Pathway upregulation

2018 ◽  
Author(s):  
Cassie Tyson
Keyword(s):  
Developmental Stages ◽  
Hedgehog Pathway ◽  
Chondrocyte Differentiation ◽  
Loss Of Function ◽  
Wild Type ◽  
Phenotypic Analysis ◽  
Growth Plate Chondrocytes ◽  
Idh Mutations ◽  
Cartilage Tumors ◽  
Deficient Mice

Cartilage tumors are the most common and terminal primary neoplasms in bone. Physiologically, bones formed through endochondral ossification are regulated by the Hedgehog pathway and Parathyroid hormone-like hormone feedback loop. The upregulation of the infamous Hedgehog pathway has been demonstrated in several non-cartilaginous neoplasms. Recently, frequent mutational events of isocitrate dehydrogenase1 (IDH1) were identified in cartilage tumors. In other neoplasms, IDH mutations produces an oncometabolite that can promote HIF1a activation, contributing to tumorigenesis. Currently, the role of IDH1 mutations in cartilage tumors remain unknown. Investigating the physiological aspect of IDH1proves useful in identifying novel therapeutic targets for cartilage tumors. IDH1 deficient and wild-type littermates, were harvested for forelimbs and hindlimbs at various developmental stages for phenotypic analysis via hematoxylin and eosin staining. Histological analysis demonstrated IDH1 homozygous deficient mice at embryonic stages exhibited dwarfism and an elongated layer of hypertrophic chondrocytes. This was verified via immunohistochemistry Type 10 Collagen staining and Quantitative PCR (qPCR) using the chondrocyte terminal differentiation marker Col10a1. Whole skeletons of IDH1 deficient mice were subjected to skeletal double staining which demonstrated delayed mineralization of underdeveloped IDH1 deficient mice contrasted with wild-type littermates. qPCR was performed to examine the status of chondrocyte differentiation through the Hedgehog pathway in cultured primarymouse growth plate chondrocytes. Interestingly, IDH1 deficient non-neoplastic cells revealed significant upregulation of Hedgehog target molecules in IDH1 deficient chondrocytes. As a result, the loss-offunction of IDH1 was identified as a potential impairment of chondrocyte differentiation and a factor towards chondrocyte tumorgenisis.

Inhibition by extracellular Na+ replacement of GRF-induced GH secretion from rat pituitary cells

1988 ◽  
Vol 254 (4) ◽  
pp. E476-E481 ◽  
Author(s):  
M. Kato ◽  
M. A. Hattori ◽  
M. Suzuki
Keyword(s):  
Anterior Pituitary ◽  
Channel Blocker ◽  
Na Channel ◽  
Pituitary Cells ◽  
Ionic Mechanism ◽  
Camp Production ◽  
Normal Medium ◽  
Gh Secretion ◽  
Rat Pituitary ◽  
Rat Pituitary Cells

To further clarify the ionic mechanism of the action of growth hormone (GH)-releasing factor (hGRF) on GH secretion, the involvement of extracellular Na+ was studied in perifused dispersed rat anterior pituitary cells. Replacing extracellular Na+ with mannitol or tris(hydroxymethyl)aminomethane (Tris+) suppressed hGRF- and dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP)-induced GH secretion. The peak responses to a 2-min application of 1 nM hGRF were 165.0 +/- 5.6 ng/ml (normal medium, mean +/- SE), 21.2 +/- 1.4 ng/ml (Na+-free, mannitol medium), and 18.0 +/- 1.7 ng/ml (Na+-free, Tris+ medium). GH secretion induced by DBcAMP was also suppressed by Na+ replacement to less than 50% of that in normal medium. However, either 15 or 30 mM KCl-stimulated GH secretion was not markedly affected by replacement of Na+ with either compound. Tetrodotoxin, a voltage-sensitive Na+ channel blocker, had no effect on either hGRF- or excess K+-induced GH secretion. cAMP production by hGRF was not greatly affected by replacing extracellular Na+. Thus extracellular Na+ plays an important role in hGRF-induced GH secretion, especially in the process after cAMP production. The involvement of cAMP-sensitive Na+ channels in hGRF-stimulated GH secretion is discussed.

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