scholarly journals ISL1 Is Necessary for Maximal Thyrotrope Response to Hypothyroidism

2015 ◽  
Vol 29 (10) ◽  
pp. 1510-1521 ◽  
Author(s):  
F. Castinetti ◽  
M. L. Brinkmeier ◽  
A. H. Mortensen ◽  
K. R. Vella ◽  
P. Gergics ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Motor Neurons ◽  
Heart Defects ◽  
Normal Serum ◽  
Early Embryogenesis ◽  
Pituitary Cells ◽  
Specific Expression ◽  
Obvious Effect ◽  
Deficient Mice ◽  
Serum Tsh

Abstract ISLET1 is a homeodomain transcription factor necessary for development of the pituitary, retina, motor neurons, heart, and pancreas. Isl1-deficient mice (Isl1−/−) die early during embryogenesis at embryonic day 10.5 due to heart defects, and at that time, they have an undersized pituitary primordium. ISL1 is expressed in differentiating pituitary cells in early embryogenesis. Here, we report the cell-specific expression of ISL1 and assessment of its role in gonadotropes and thyrotropes. Isl1 expression is elevated in pituitaries of Cga−/− mice, a model of hypothyroidism with thyrotrope hypertrophy and hyperplasia. Thyrotrope-specific disruption of Isl1 with Tshb-cre is permissive for normal serum TSH, but T4 levels are decreased, suggesting decreased thyrotrope function. Inducing hypothyroidism in normal mice causes a reduction in T4 levels and dramatically elevated TSH response, but mice with thyrotrope-specific disruption of Isl1 have a blunted TSH response. In contrast, deletion of Isl1 in gonadotropes with an Lhb-cre transgene has no obvious effect on gonadotrope function or fertility. These results show that ISL1 is necessary for maximal thyrotrope response to hypothyroidism, in addition to its role in development of Rathke's pouch.

scholarly journals Gene Targeting Reveals a Widespread Role for the High-Mobility-Group Transcription Factor Sox11 in Tissue Remodeling

2004 ◽  
Vol 24 (15) ◽  
pp. 6635-6644 ◽  
Author(s):  
Elisabeth Sock ◽  
Stefanie D. Rettig ◽  
Janna Enderich ◽  
Michael R. Bösl ◽  
Ernst R. Tamm ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Heart Defects ◽  
High Mobility ◽  
Tissue Remodeling ◽  
Double Outlet Right Ventricle ◽  
High Mobility Group ◽  
Common Trunk ◽  
Developmental Defects ◽  
Malformation Syndromes ◽  
Deficient Mice

ABSTRACT The high-mobility-group domain-containing transcription factor Sox11 is expressed transiently during embryonic development in many tissues that undergo inductive remodeling. Here we have analyzed the function of Sox11 by gene deletion in the mouse. Sox11-deficient mice died at birth from congenital cyanosis, likely resulting from heart defects. These included ventricular septation defects and outflow tract malformations that ranged from arterial common trunk to a condition known as double outlet right ventricle. Many other organs that normally express Sox11 also exhibited severe developmental defects. We observed various craniofacial and skeletal malformations, asplenia, and hypoplasia of the lung, stomach, and pancreas. Eyelids and the abdominal wall did not close properly in some Sox11-deficient mice. This phenotype suggests a prime function for Sox11 in tissue remodeling and identifies SOX11 as a potentially mutated gene in corresponding human malformation syndromes.

scholarly journals The transcription factor GATA3 is a downstream effector of Hoxb1 specification in rhombomere 4

Development ◽  
1999 ◽  
Vol 126 (23) ◽  
pp. 5523-5531 ◽  
Author(s):  
I. Pata ◽  
M. Studer ◽  
J.H. van Doorninck ◽  
J. Briscoe ◽  
S. Kuuse ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Motor Neurons ◽  
Ectopic Expression ◽  
Downstream Effector ◽  
Gata3 Expression ◽  
Efferent Neurons ◽  
Facial Branchiomotor Neurons ◽  
Deficient Mice ◽  
Rhombomere 4

In this paper, we show that the transcription factor GATA3 is dynamically expressed during hindbrain development. Function of GATA3 in ventral rhombomere (r) 4 is dependent on functional GATA2, which in turn is under the control of Hoxb1. In particular, the absence of Hoxb1 results in the loss of GATA2 expression in r4 and the absence of GATA2 results in the loss of GATA3 expression. The lack of GATA3 expression in r4 inhibits the projection of contralateral vestibuloacoustic efferent neurons and the migration of facial branchiomotor neurons similar to Hoxb1-deficient mice. Ubiquitous expression of Hoxb1 in the hindbrain induces ectopic expression of GATA2 and GATA3 in ventral r2 and r3. These findings demonstrate that GATA2 and GATA3 lie downstream of Hoxb1 and provide the first example of Hox pathway transcription factors within a defined population of vertebrate motor neurons.

Defective thyroglobulin storage in LDL receptor-associated protein-deficient mice

2006 ◽  
Vol 290 (4) ◽  
pp. C1160-C1167 ◽  
Author(s):  
Simonetta Lisi ◽  
Roberta Botta ◽  
Aldo Pinchera ◽  
A. Bernard Collins ◽  
Samuel Refetoff ◽  
...  
Keyword(s):  
Molecular Chaperone ◽  
Hormone Secretion ◽  
Ldl Receptor ◽  
Normal Serum ◽  
Wild Type ◽  
Histological Features ◽  
Receptor Associated Protein ◽  
Concomitant Reduction ◽  
Deficient Mice ◽  
Serum Tsh

The molecular chaperone receptor-associated protein (RAP) is required for biosynthesis of megalin, an endocytic receptor for follicular thyroglobulin (Tg), the thyroid hormone precursor. RAP also binds to Tg itself, suggesting that it may affect Tg trafficking in various manners. To elucidate RAP function, we have studied the thyroid phenotype in RAP-knockout (RAP-KO) mice and found a reduction of Tg aggregates into thyroid follicles. Serum Tg levels were significantly increased compared with those of wild-type (WT) mice, suggesting a directional alteration of Tg secretion. In spite of these abnormalities, hormone secretion was maintained as indicated by normal serum thyroxine levels. Because Tg in thyroid extracts from RAP-KO mice contained thyroxine residues as in WT mice, we concluded that in RAP-KO mice, follicular Tg, although reduced, was nevertheless sufficient to provide normal hormone secretion. Serum TSH was increased in RAP-KO mice, and although no thyroid enlargement was observed, some histological features resembling early goiter were present. Megalin was decreased in RAP-KO mice, but this did not affect thyroid function, probably because of the concomitant reduction of follicular Tg. In conclusion, RAP is required for the establishment of Tg reservoirs, but its absence does not affect hormone secretion.

scholarly journals The 26-Amino Acid ß-Motif of the Pit-1ß Transcription Factor Is a Dominant and Independent Repressor Domain

2009 ◽  
Vol 23 (9) ◽  
pp. 1371-1384 ◽  
Author(s):  
Matthew D. Jonsen ◽  
Dawn L. Duval ◽  
Arthur Gutierrez-Hartmann
Keyword(s):  
Transcription Factor ◽  
Amino Acid ◽  
Promoter Activity ◽  
Pituitary Cells ◽  
Heterologous Promoter ◽  
Specific Expression ◽  
Dna Binding Sites ◽  
Repressor Activity ◽  
Sequence Position

Abstract The POU-homeodomain transcription factor Pit-1 governs the pituitary cell-specific expression of Pit-1, GH, prolactin (PRL), and TSHß genes. Alternative splicing generates Pit-1ß, which contains a 26-amino acid ß-domain inserted at amino acid 48, in the middle of the Pit-1 transcription activation domain (TAD). Pit-1ß represses GH, PRL, and TSHß promoters in a pituitary-specific manner, because Pit-1ß activates these same promoters in HeLa nonpituitary cells. Here we comprehensively analyze the role of ß-domain sequence, position, and context, to elucidate the mechanism of ß-dependent repression. Repositioning the ß-motif to the Pit-1 amino terminus, hinge, linker, and carboxyl terminus did not affect its ability to repress basal rat (r) PRL promoter activity in GH4 pituitary cells, but all lost the ability to repress Ras-induced rPRL promoter activity. To determine whether ß-domain repression is independent of Pit-1 protein and DNA binding sites, we generated Gal4-Pit-1TAD, Gal4-Pit-1ßTAD, and Gal4-ß-domain fusions and demonstrated that the ß-motif is sufficient to actively repress VP16-mediated transcription of a heterologous promoter. Moreover, ß-domain point mutants had the same effect whether fused to Gal4 or within the context of intact Pit-1ß. Surprisingly, Gal4-ß repression lost histone deacetylase sensitivity and pituitary specificity. Taken together, these results reveal that the ß-motif is a context-independent, modular, transferable, and dominant repressor domain, yet the ß-domain repressor activity within Pit-1ß contains cell type, promoter, and Pit-1 protein context dependence.

scholarly journals MON-715 How Heterogeneous Are Pituitary Thyrotropes?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lindsey Anne Dudley ◽  
Alexandre Zacharie Daley ◽  
Amanda Helen Mortensen ◽  
Rachna Sridhar ◽  
Michelle Brinkmeier ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Pituitary Gland ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Newborn Mice ◽  
Pituitary Development ◽  
Helix Loop Helix ◽  
Species Specific ◽  
Deficient Mice

Abstract Many transcription factors have been identified that are important for specification and differentiation of the hormone-producing cells of the pituitary gland. For example, POU1F1 is essential for differentiation of thyrotropes, somatotropes, and lactotropes. GATA2 is important for differentiation of both thyrotropes and gonadotropes, and NR5A1 drives gonadotrope differentiation. It is not known whether additional transcription factors are involved in thyrotrope specification. A few POU1F1-independent thyrotropes arise during development at the rostral tip of the pituitary gland, but the majority of thyrotropes are POU1F1-dependent and arise in the caudo-medial area of the anterior pituitary gland. Pou1f1-deficient mice lack this major, critical type of thyrotropes and are severely hypothyroid. Several pieces of evidence suggest that the caudo-medial population of thyrotropes is heterogeneous. First, NR5A1-positive cells exist that express both TSH and FSH during pituitary development. Second, Pou1f1 mRNA is detected in only about half of pituitary cells immuno-positive for TSH. Third, the transcription factor ISL1 is only detected in a fraction of developing thyrotropes. The Helix-Loop-Helix transcription factor ASCL1 is critical for zebrafish pituitary development, but there are conflicting data about its role in pituitary thyrotrope specification in mice. To quantify the role of ASCL1 in thyrotrope development we carried out immunostaining for TSH in pituitaries of Ascl1 deficient mice in late gestation. We did not detect any reduction in TSH immuno-reactive cells at this time, suggesting there are species-specific differences in the requirement of ASCL1 in the developing pituitary. To systematically assess and quantify the heterogeneity of thyrotropes for transcription factor expression, we performed co-immunostaining for TSH and various transcription factors in pituitaries of newborn mice. We found that approximately 75% of TSH-positive cells in the caudo-medial region of the pituitary express POU1F1, and the majority express GATA2. We detected a small portion of cells co-expressing NR5A1 and TSH at this time. To confirm our immunostaining results, we analyzed data from single cell RNA sequencing of postnatal thyrotropes. Three robust clusters of thyrotropes were identified. Approximately 80% expressed Gata2, 85% expressed Pou1f1, and roughly 15% expressed Nr5a1. Taken together, the protein and RNA analysis support that thyrotrope heterogeneity exists during development. The functional significance of this heterogeneity and its variation during development will be the subject of future investigation.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals Tissue-specific expression of B7x protects from CD4 T cell–mediated autoimmunity

2011 ◽  
Vol 208 (8) ◽  
pp. 1683-1694 ◽  
Author(s):  
Joyce Wei ◽  
P’ng Loke ◽  
Xingxing Zang ◽  
James P. Allison
Keyword(s):  
T Cells ◽  
Pancreatic Islets ◽  
Peripheral Tolerance ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Specific Expression ◽  
Tissue Specific ◽  
Disease Induction ◽  
Deficient Mice ◽  
Experimental Autoimmune

B7x, an inhibitory member of the B7/CD28 superfamily, is highly expressed in a broad range of nonhematopoietic organs, suggesting a role in maintaining peripheral tolerance. As endogenous B7x protein is expressed in pancreatic islets, we investigated whether the molecule inhibits diabetogenic responses. Transfer of disease-inducing BDC2.5 T cells into B7x-deficient mice resulted in a more aggressive form of diabetes than in wild-type animals. This exacerbation of disease correlated with higher frequencies of islet-infiltrating Th1 and Th17 cells. Conversely, local B7x overexpression inhibited the development of autoimmunity, as crossing diabetes-susceptible BDC2.5/B6g7 mice to animals overexpressing B7x in pancreatic islets abrogated disease induction. This protection was caused by the inhibition of IFN-γ production by CD4 T cells and not to a skewing or expansion of Th2 or regulatory T cells. The suppressive function of B7x was also supported by observations from another autoimmune model, experimental autoimmune encephalomyelitis, in which B7x-deficient mice developed exacerbated disease in comparison with wild-type animals. Analysis of central nervous system–infiltrating immune cells revealed that the loss of endogenous B7x resulted in expanded Th1 and Th17 responses. Data from these two autoimmune models provide evidence that B7x expression in the periphery acts as an immune checkpoint to prevent tissue-specific autoimmunity.

The restricted promoter activity of the liver transcription factor hepatocyte nuclear factor 3 beta involves a cell-specific factor and positive autoactivation

1992 ◽  
Vol 12 (2) ◽  
pp. 552-562
Author(s):  
L Pani ◽  
X B Quian ◽  
D Clevidence ◽  
R H Costa
Keyword(s):  
Transcription Factor ◽  
Promoter Activity ◽  
Binding Activity ◽  
Specific Factor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Cell Type ◽  
Specific Expression ◽  
Cell Type Specific Expression ◽  
Cell Type Specific

The transcription factor hepatocyte nuclear factor 3 (HNF-3) is involved in the coordinate expression of several liver genes. HNF-3 DNA binding activity is composed of three different liver proteins which recognize the same DNA site. The HNF-3 proteins (designated alpha, beta, and gamma) possess homology in the DNA binding domain and in several additional regions. To understand the cell-type-specific expression of HNF-3 beta, we have defined the regulatory sequences that elicit hepatoma-specific expression. Promoter activity requires -134 bp of HNF-3 beta proximal sequences and binds four nuclear proteins, including two ubiquitous factors. One of these promoter sites interacts with a novel cell-specific factor, LF-H3 beta, whose binding activity correlates with the HNF-3 beta tissue expression pattern. Furthermore, there is a binding site for the HNF-3 protein within its own promoter, suggesting that an autoactivation mechanism is involved in the establishment of HNF-3 beta expression. We propose that both the LF-H3 beta and HNF-3 sites play an important role in the cell-type-specific expression of the HNF-3 beta transcription factor.

Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression

1994 ◽  
Vol 14 (11) ◽  
pp. 7276-7284
Author(s):  
W Zhong ◽  
J Mirkovitch ◽  
J E Darnell
Keyword(s):  
Transcription Factor ◽  
Transgenic Mice ◽  
Transient Transfection ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Distal Enhancer ◽  
Specific Expression ◽  
Tissue Specific ◽  
Hypersensitive Sites ◽  
Hepatocyte Nuclear Factor 4

Hepatocyte nuclear factor 4 (HNF-4) is a liver-enriched transcription factor and a member of the steroid hormone receptor superfamily. HNF-4 is required for the hepatoma-specific expression of HNF-1 alpha, another liver-enriched transcription factor, suggesting the early participation of HNF-4 in development. To prepare for further study of HNF-4 in development, the tissue-specific expression of the mouse HNF-4 gene was studied by analyzing the promoter region for required DNA elements. DNase-hypersensitive sites in the gene in liver and kidney tissues were found in regions both distal and proximal to the RNA start that were absent in tissues in which HNF-4 expression did not occur. By use of reporter constructs in transient-transfection assays and with transgenic mice, a region sufficient to drive liver-specific expression of HNF-4 was identified. While an HNF-1 binding site between bp -98 and -68 played an important role in the hepatoma-specific promoter activity of HNF-4 in transient-transfection assays, it was not sufficient for the liver-specific expression of a reporter gene in transgenic mice. Distal enhancer elements indicated by the presence of DNase I-hypersensitive sites at kb -5.5 and -6.5, while not functional in transient-transfection assays, were required for the correct expression of the mouse HNF-4 gene in animals.

scholarly journals IRF9 Prevents CD8+ T Cell Exhaustion in an Extrinsic Manner during Acute Lymphocytic Choriomeningitis Virus Infection

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Magdalena Huber ◽  
Tamara Suprunenko ◽  
Thomas Ashhurst ◽  
Felix Marbach ◽  
Hartmann Raifer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Viral Infection ◽  
Chronic Infection ◽  
Acute Infection ◽  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Deficient Mice

ABSTRACT Effective CD8+ T cell responses play an important role in determining the course of a viral infection. Overwhelming antigen exposure can result in suboptimal CD8+ T cell responses, leading to chronic infection. This altered CD8+ T cell differentiation state, termed exhaustion, is characterized by reduced effector function, upregulation of inhibitory receptors, and altered expression of transcription factors. Prevention of overwhelming antigen exposure to limit CD8+ T cell exhaustion is of significant interest for the control of chronic infection. The transcription factor interferon regulatory factor 9 (IRF9) is a component of type I interferon (IFN-I) signaling downstream of the IFN-I receptor (IFNAR). Using acute infection of mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong, we show here that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and IFN-I and by controlling levels of IRF7, a transcription factor essential for IFN-I production. Infection of IRF9- or IFNAR-deficient mice led to a loss of early restriction of viral replication and impaired antiviral responses in dendritic cells, resulting in CD8+ T cell exhaustion and chronic infection. Differences in the antiviral activities of IRF9- and IFNAR-deficient mice and dendritic cells provided further evidence of IRF9-independent IFN-I signaling. Thus, our findings illustrate a CD8+ T cell-extrinsic function for IRF9, as a signaling factor downstream of IFNAR, in preventing overwhelming antigen exposure resulting in CD8+ T cell exhaustion and, ultimately, chronic infection. IMPORTANCE During early viral infection, overwhelming antigen exposure can cause functional exhaustion of CD8+ T cells and lead to chronic infection. Here we show that the transcription factor interferon regulatory factor 9 (IRF9) plays a decisive role in preventing CD8+ T cell exhaustion. Using acute infection of mice with LCMV strain Armstrong, we found that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and Irf7, encoding a transcription factor crucial for type I interferon (IFN-I) production, as well as by controlling the levels of IFN-I. Infection of IRF9-deficient mice led to a chronic infection that was accompanied by CD8+ T cell exhaustion due to defects extrinsic to T cells. Our findings illustrate an essential role for IRF9, as a mediator downstream of IFNAR, in preventing overwhelming antigen exposure causing CD8+ T cell exhaustion and leading to chronic viral infection.

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