The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
George P. Chrousos - One of the best experts on this subject based on the ideXlab platform.
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stress related and circadian secretion and Target Tissue actions of glucocorticoids impact on health
Frontiers in Endocrinology, 2017Co-Authors: Tomoshige Kino, George P. Chrousos, Nicolas C Nicolaides, Evangelia CharmandariAbstract:Living organisms are highly complex systems that must maintain a dynamic equilibrium or homeostasis that requires energy to be sustained. Stress is a state in which several extrinsic or intrinsic disturbing stimuli, the stressors, threaten, or are perceived as threatening, homeostasis. To achieve homeostasis against the stressors, organisms have developed a highly sophisticated system, the stress system, which provides neuroendocrine adaptive responses, to restore homeostasis. These responses must be appropriate in terms of size and/or duration; otherwise, they may sustain life but be associated with detrimental effects on numerous physiologic functions of the organism, leading to a state of disease-causing disturbed homeostasis or cacostasis. In addition to facing a broad spectrum of external and/or internal stressors, organisms are subject to recurring environmental changes associated with the rotation of the planet around itself and its revolution around the sun. To adjust their homeostasis and to synchronize their activities to day/night cycles, organisms have developed an evolutionarily conserved biologic system, the “clock” system, which influences several physiologic functions in a circadian fashion. Accumulating evidence suggests that the stress system is intimately related to the circadian clock system, with dysfunction of the former resulting in dysregulation of the latter, and vice versa. In this review, we describe the functional components of the two systems, we discuss their multilevel interactions, and we present how excessive or prolonged activity of the stress system affects the circadian rhythm of glucocorticoid secretion and Target Tissue effects.
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peripheral clock regulates Target Tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man
PLOS ONE, 2011Co-Authors: George P. Chrousos, Evangelia Charmandari, George I Lambrou, Aikaterini N Pavlaki, Hisashi Koide, Tomoshige KinoAbstract:Context and Objective: Circulating cortisol fluctuates diurnally under the control of the ‘‘master’’ circadian CLOCK, while the peripheral ‘‘slave’’ counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR) at local glucocorticoid Target Tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral Tissues to glucocorticoids in humans. Design and Participants: We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoidresponsive genes in peripheral blood mononuclear cells (PBMCs) obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs) as non-synchronized controls. Results: GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock- and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo. Conclusions: Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a Target-Tissue, genespecific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing Tissue sensitivity to glucocorticoids in the morning and increasing it at night.
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Circadian CLOCK-mediated Regulation of Target-Tissue Sensitivity to Glucocorticoids: Implications for Cardiometabolic Diseases
Endocrine development, 2010Co-Authors: Tomoshige Kino, George P. ChrousosAbstract:Glucocorticoids, the end-products of the hypothalamic-pituitary-adrenal (HPA) axis, influence the functions of virtually all organs and Tissues through the nuclear glucocorticoid receptor (GR). Circulating levels of glucocorticoids fluctuate naturally in a circadian fashion under the strong influence of the hypothalamic suprachiasmatic nucleus (SCN) circadian CLOCK system, and regulate the transcriptional activity of the GR in the brain and peripheral Target Tissues. We recently reported that the basic helix-loop-helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the “lysine cluster” located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a Target Tissue counter regulatory mechanism to the diurnally fluctuating circulating glucocorticoids. Interestingly, mild evening elevations of cortisol, as occurs in chronic stress situations, and frequent uncoupling of the SCN CLOCK-directed HPA axis from the daily oscillation of Target Tissue sensitivity to glucocorticoids, as happens in trans-time zone travel and night shift work, produce functional hypercortisolism and, hence, multiple components of the metabolic syndrome with resultant cardiovascular complications.
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the hypothalamic pituitary adrenal axis of prairie voles microtus ochrogaster evidence for Target Tissue glucocorticoid resistance
General and Comparative Endocrinology, 1997Co-Authors: Susan E Taymans, Courtney A Devries, Brigid M Devries, Randy J Nelson, Theodore C Friedman, Margaret De Castro, Sevilla D Deterawadleigh, Sue C Carter, George P. ChrousosAbstract:Basal plasma corticosterone levels in prairie voles (Microtus ochrogaster) are extremely high, in the absence of any apparent negative consequences of glucocorticoid excess. We tested the hypothesis that prairie voles are a novel rodent model of Target Tissue resistance to glucocorticoids. Prairie voles had a significantly higher adrenal-to-body weight ratio, 5- to 10-fold greater basal plasma corticosterone, and 2- to 3-fold greater basal plasma ACTH concentrations than montane voles (Microtus montanus) and rats. While plasma corticosterone binding globulin (CBG) was 2-fold higher in prairie voles than in rats, both estimated and directly measured plasma free corticosterone were significantly higher in prairie voles than in rats. Plasma corticosterone levels in prairie voles were responsive to both circadian cues and a stressor, but were resistant to suppression by the synthetic glucocorticoid, dexamethasone (DEX). Western blots of brain and liver protein extracts, using a glucocorticoid receptor (GR) antibody, revealed the presence of a ≈97 kDa immunoreactive band, the expected size for GR. Binding assays revealed significantly lower DEX affinity of corticosteroid receptors (CR) in cytosol of prairie vole brain and liver than that in the same Tissues in rats. We conclude that prairie voles are a novel rodent model of glucocorticoid resistance, and that decreased affinity of CR for ligand might be partially responsible for this phenomenon.
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Article No. GC966849 The Hypothalamic–Pituitary–Adrenal Axis of Prairie Voles (Microtus ochrogaster): Evidence for Target Tissue Glucocorticoid Resistance
1996Co-Authors: Susan E Taymans, Courtney A Devries, Brigid M Devries, Theodore C Friedman, Margaret De Castro, Sue C Carter, Y J. Nelson, Sevilla Detera-wadleigh, George P. ChrousosAbstract:Basal plasma corticosterone levels in prairie voles (Microtus ochrogaster) are extremely high, in the absence of any apparent negative consequences of glucocorticoid excess. We tested the hypothesis that prairie voles are a novel rodent model of Target Tissue resistance to glucocorticoids. Prairie voles had a significantly higher adrenal-tobody weight ratio, 5- to 10-fold greater basal plasma corticosterone, and 2- to 3-fold greater basal plasma ACTH concentrations than montane voles (Microtus montanus) and rats. While plasma corticosterone binding globulin (CBG) was 2-fold higher in prairie voles than in rats, both estimated and directly measured plasma free corticosterone were significantly higher in prairie voles than in rats. Plasma corticosterone levels in prairie voles were responsive to both circadian cues and a stressor, but were resistant to suppression by the synthetic glucocorticoid, dexamethasone (DEX). Western blots of brain and liver protein extracts, using a glucocorticoid receptor (GR) antibody, revealed the presence of a D97 kDa immunoreactive band, the expected size for GR. Binding assays revealed significantly lower DEX affinity of corticosteroid receptors (CR) in cytosol of prairie vole
Wenjun Zhang - One of the best experts on this subject based on the ideXlab platform.
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a review of radiofrequency ablation large Target Tissue necrosis and mathematical modelling
Physica Medica, 2016Co-Authors: Bing Zhang, Michael A J Moser, Edwin Zhang, Yigang Luo, Wenjun Zhang, Changli LiuAbstract:Radiofrequency ablation (RFA) is an effective clinical method for tumour ablation with minimum intrusiveness. However, the use of RFA is mostly restricted to small tumours, especially those <3cm in diameter. This paper discusses the state-of-the-art of RFA, drawn from experimental and clinical results, for large tumours (i.e. ⩾3cm in diameter). In particular, the paper analyses clinical results related to Target Tissue necrosis (TTN) and mathematical modelling of the RFA procedure to understand the mechanism whereby the TTN is limited to under 3cm with RFA. This paper also discusses a strategy of controlling of the temperature of Target Tissue in the RFA procedure with the state-of-art device, which has the potential to increase the size of TTN. This paper ends with a discussion of some future ideas to solve the so-called 3-cm problem with RFA.
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A review of radiofrequency ablation: Large Target Tissue necrosis and mathematical modelling
Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Associ, 2016Co-Authors: Bing Zhang, Michael A J Moser, Yigang Luo, Changli Liu, Edwin M. Zhang, Wenjun ZhangAbstract:Radiofrequency ablation (RFA) is an effective clinical method for tumour ablation with minimum intrusiveness. However, the use of RFA is mostly restricted to small tumours, especially those
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Numerical analysis of the relationship between the area of Target Tissue necrosis and the size of Target Tissue in liver tumours with pulsed radiofrequency ablation.
International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology North American Hyperthermia Group, 2015Co-Authors: Bing Zhang, Michael A J Moser, Yigang Luo, Edwin M. Zhang, Wenjun ZhangAbstract:AbstractPurpose: Radiofrequency ablation (RFA) is currently restricted to the treatment of Target Tissues with a small size (
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On Understanding of the Limiting Factors in Radiofrequency Ablation on Target Tissue Necrosis Volume
IFMBE Proceedings, 2015Co-Authors: Bing Zhang, Michael A J Moser, E. M. Zhang, Y. Luo, Wenjun ZhangAbstract:The aim of this study was to analyze six limiting factors that may be responsible for Target Tissue necrosis (TTN) generation during the procedure of radiofrequency ablation (RFA). A comprehensive finite element (FE) model was built to collect the data of TTN generated in a liver Tissue by using a commercial available RFA system. The model was validated by comparison of results with in vitro experiment in a literature. Six limiting factors were analyzed using a statistical method. Sixteen RFA experiments were performed, in which the TTN volume was considered as a response variable along with the six control factors. The TTN volumes obtained from the 16 simulations were quite different, ranging from 7.749 to 8433.931 mm 3 . The applied voltage (V), the frequency (f), the length (L) of the RF electrode, the chilled fluid temperature (T), the large blood vessel (d) in the proximity to Target Tissue and the ablation duration (t) account for approximately 78.21%, 9.93%, 2.91%, 0.01%, 4.64%, and 0.08%, respectively, of the effect on the TTN volume. The findings from the present study suggest that the applied voltage (V) and the frequency (f), followed by the large blood vessel (d) in proximity to Target Tissue, have the highest effect on the TTN volume.
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study of the relationship between the Target Tissue necrosis volume and the Target Tissue size in liver tumours using two compartment finite element rfa modelling
International Journal of Hyperthermia, 2014Co-Authors: Bing Zhang, Michael A J Moser, Edwin Zhang, Yigang Luo, Hongbo Zhang, Wenjun ZhangAbstract:AbstractPurpose: The aim of this study was to investigate the relationship between the Target Tissue necrosis volume and the Target Tissue size during the radiofrequency ablation (RFA) procedure.Materials and methods: The Target Tissues with four different sizes (dxy = 20, 25, 30 and 35 mm) were modelled using a two-compartment radiofrequency ablation model. Different voltages were applied to seek the maximum Target Tissue necrosis volume for each Target Tissue size. The first roll-off occurrence or the standard ablation time (12 min) was taken as the sign for the termination of the RFA procedure.Results: Four different maximum voltages without the roll-off occurrence were found for the four different sizes of Target Tissues (dxy = 20, 25, 30 and 35 mm), and they were 36.6, 35.4, 33.9 and 32.5 V, respectively. The Target Tissues with diameters of 20, 25 mm can be cleanly ablated at their own maximum voltages applied (MVA) but the same finding was not found for the 35-mm Target Tissue. For the Target tissu...
Susan E Taymans - One of the best experts on this subject based on the ideXlab platform.
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the hypothalamic pituitary adrenal axis of prairie voles microtus ochrogaster evidence for Target Tissue glucocorticoid resistance
General and Comparative Endocrinology, 1997Co-Authors: Susan E Taymans, Courtney A Devries, Brigid M Devries, Randy J Nelson, Theodore C Friedman, Margaret De Castro, Sevilla D Deterawadleigh, Sue C Carter, George P. ChrousosAbstract:Basal plasma corticosterone levels in prairie voles (Microtus ochrogaster) are extremely high, in the absence of any apparent negative consequences of glucocorticoid excess. We tested the hypothesis that prairie voles are a novel rodent model of Target Tissue resistance to glucocorticoids. Prairie voles had a significantly higher adrenal-to-body weight ratio, 5- to 10-fold greater basal plasma corticosterone, and 2- to 3-fold greater basal plasma ACTH concentrations than montane voles (Microtus montanus) and rats. While plasma corticosterone binding globulin (CBG) was 2-fold higher in prairie voles than in rats, both estimated and directly measured plasma free corticosterone were significantly higher in prairie voles than in rats. Plasma corticosterone levels in prairie voles were responsive to both circadian cues and a stressor, but were resistant to suppression by the synthetic glucocorticoid, dexamethasone (DEX). Western blots of brain and liver protein extracts, using a glucocorticoid receptor (GR) antibody, revealed the presence of a ≈97 kDa immunoreactive band, the expected size for GR. Binding assays revealed significantly lower DEX affinity of corticosteroid receptors (CR) in cytosol of prairie vole brain and liver than that in the same Tissues in rats. We conclude that prairie voles are a novel rodent model of glucocorticoid resistance, and that decreased affinity of CR for ligand might be partially responsible for this phenomenon.
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Article No. GC966849 The Hypothalamic–Pituitary–Adrenal Axis of Prairie Voles (Microtus ochrogaster): Evidence for Target Tissue Glucocorticoid Resistance
1996Co-Authors: Susan E Taymans, Courtney A Devries, Brigid M Devries, Theodore C Friedman, Margaret De Castro, Sue C Carter, Y J. Nelson, Sevilla Detera-wadleigh, George P. ChrousosAbstract:Basal plasma corticosterone levels in prairie voles (Microtus ochrogaster) are extremely high, in the absence of any apparent negative consequences of glucocorticoid excess. We tested the hypothesis that prairie voles are a novel rodent model of Target Tissue resistance to glucocorticoids. Prairie voles had a significantly higher adrenal-tobody weight ratio, 5- to 10-fold greater basal plasma corticosterone, and 2- to 3-fold greater basal plasma ACTH concentrations than montane voles (Microtus montanus) and rats. While plasma corticosterone binding globulin (CBG) was 2-fold higher in prairie voles than in rats, both estimated and directly measured plasma free corticosterone were significantly higher in prairie voles than in rats. Plasma corticosterone levels in prairie voles were responsive to both circadian cues and a stressor, but were resistant to suppression by the synthetic glucocorticoid, dexamethasone (DEX). Western blots of brain and liver protein extracts, using a glucocorticoid receptor (GR) antibody, revealed the presence of a D97 kDa immunoreactive band, the expected size for GR. Binding assays revealed significantly lower DEX affinity of corticosteroid receptors (CR) in cytosol of prairie vole
Bing Zhang - One of the best experts on this subject based on the ideXlab platform.
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a review of radiofrequency ablation large Target Tissue necrosis and mathematical modelling
Physica Medica, 2016Co-Authors: Bing Zhang, Michael A J Moser, Edwin Zhang, Yigang Luo, Wenjun Zhang, Changli LiuAbstract:Radiofrequency ablation (RFA) is an effective clinical method for tumour ablation with minimum intrusiveness. However, the use of RFA is mostly restricted to small tumours, especially those <3cm in diameter. This paper discusses the state-of-the-art of RFA, drawn from experimental and clinical results, for large tumours (i.e. ⩾3cm in diameter). In particular, the paper analyses clinical results related to Target Tissue necrosis (TTN) and mathematical modelling of the RFA procedure to understand the mechanism whereby the TTN is limited to under 3cm with RFA. This paper also discusses a strategy of controlling of the temperature of Target Tissue in the RFA procedure with the state-of-art device, which has the potential to increase the size of TTN. This paper ends with a discussion of some future ideas to solve the so-called 3-cm problem with RFA.
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A review of radiofrequency ablation: Large Target Tissue necrosis and mathematical modelling
Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Associ, 2016Co-Authors: Bing Zhang, Michael A J Moser, Yigang Luo, Changli Liu, Edwin M. Zhang, Wenjun ZhangAbstract:Radiofrequency ablation (RFA) is an effective clinical method for tumour ablation with minimum intrusiveness. However, the use of RFA is mostly restricted to small tumours, especially those
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Numerical analysis of the relationship between the area of Target Tissue necrosis and the size of Target Tissue in liver tumours with pulsed radiofrequency ablation.
International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology North American Hyperthermia Group, 2015Co-Authors: Bing Zhang, Michael A J Moser, Yigang Luo, Edwin M. Zhang, Wenjun ZhangAbstract:AbstractPurpose: Radiofrequency ablation (RFA) is currently restricted to the treatment of Target Tissues with a small size (
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On Understanding of the Limiting Factors in Radiofrequency Ablation on Target Tissue Necrosis Volume
IFMBE Proceedings, 2015Co-Authors: Bing Zhang, Michael A J Moser, E. M. Zhang, Y. Luo, Wenjun ZhangAbstract:The aim of this study was to analyze six limiting factors that may be responsible for Target Tissue necrosis (TTN) generation during the procedure of radiofrequency ablation (RFA). A comprehensive finite element (FE) model was built to collect the data of TTN generated in a liver Tissue by using a commercial available RFA system. The model was validated by comparison of results with in vitro experiment in a literature. Six limiting factors were analyzed using a statistical method. Sixteen RFA experiments were performed, in which the TTN volume was considered as a response variable along with the six control factors. The TTN volumes obtained from the 16 simulations were quite different, ranging from 7.749 to 8433.931 mm 3 . The applied voltage (V), the frequency (f), the length (L) of the RF electrode, the chilled fluid temperature (T), the large blood vessel (d) in the proximity to Target Tissue and the ablation duration (t) account for approximately 78.21%, 9.93%, 2.91%, 0.01%, 4.64%, and 0.08%, respectively, of the effect on the TTN volume. The findings from the present study suggest that the applied voltage (V) and the frequency (f), followed by the large blood vessel (d) in proximity to Target Tissue, have the highest effect on the TTN volume.
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study of the relationship between the Target Tissue necrosis volume and the Target Tissue size in liver tumours using two compartment finite element rfa modelling
International Journal of Hyperthermia, 2014Co-Authors: Bing Zhang, Michael A J Moser, Edwin Zhang, Yigang Luo, Hongbo Zhang, Wenjun ZhangAbstract:AbstractPurpose: The aim of this study was to investigate the relationship between the Target Tissue necrosis volume and the Target Tissue size during the radiofrequency ablation (RFA) procedure.Materials and methods: The Target Tissues with four different sizes (dxy = 20, 25, 30 and 35 mm) were modelled using a two-compartment radiofrequency ablation model. Different voltages were applied to seek the maximum Target Tissue necrosis volume for each Target Tissue size. The first roll-off occurrence or the standard ablation time (12 min) was taken as the sign for the termination of the RFA procedure.Results: Four different maximum voltages without the roll-off occurrence were found for the four different sizes of Target Tissues (dxy = 20, 25, 30 and 35 mm), and they were 36.6, 35.4, 33.9 and 32.5 V, respectively. The Target Tissues with diameters of 20, 25 mm can be cleanly ablated at their own maximum voltages applied (MVA) but the same finding was not found for the 35-mm Target Tissue. For the Target tissu...
Warren G. Tourtellotte - One of the best experts on this subject based on the ideXlab platform.
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a neuron autonomous role for the familial dysautonomia gene elp1 in sympathetic and sensory Target Tissue innervation
Development, 2014Co-Authors: Marisa Z Jackson, Katherine Gruner, Charles Qin, Warren G. TourtellotteAbstract:Familial dysautonomia (FD) is characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human ELP1/IKBKAP gene. Elp1 is a subunit of the hetero-hexameric transcriptional elongator complex, but how it functions in disease-vulnerable neurons is unknown. Conditional knockout mice were generated to characterize the role of Elp1 in migration, differentiation and survival of migratory neural crest (NC) progenitors that give rise to sympathetic and sensory neurons. Loss of Elp1 in NC progenitors did not impair their migration, proliferation or survival, but there was a significant impact on post-migratory sensory and sympathetic neuron survival and Target Tissue innervation. Ablation of Elp1 in post-migratory sympathetic neurons caused highly abnormal Target Tissue innervation that was correlated with abnormal neurite outgrowth/branching and abnormal cellular distribution of soluble tyrosinated α-tubulin in Elp1-deficient primary sympathetic and sensory neurons. These results indicate that neuron loss and physiologic impairment in FD is not a consequence of abnormal neuron progenitor migration, differentiation or survival. Rather, loss of Elp1 leads to neuron death as a consequence of failed Target Tissue innervation associated with impairments in cytoskeletal regulation.
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a sympathetic neuron autonomous role for egr3 mediated gene regulation in dendrite morphogenesis and Target Tissue innervation
The Journal of Neuroscience, 2013Co-Authors: David H. Quach, Katherine Gruner, Michelle Oliveirafernandes, Warren G. TourtellotteAbstract:Egr3 is a nerve growth factor (NGF)-induced transcriptional regulator that is essential for normal sympathetic nervous system development. Mice lacking Egr3 in the germline have sympathetic Target Tissue innervation abnormalities and physiologic sympathetic dysfunction similar to humans with dysautonomia. However, since Egr3 is widely expressed and has pleiotropic function, it has not been clear whether it has a role within sympathetic neurons and if so, what Target genes it regulates to facilitate Target Tissue innervation. Here, we show that Egr3 expression within sympathetic neurons is required for their normal innervation since isolated sympathetic neurons lacking Egr3 have neurite outgrowth abnormalities when treated with NGF and mice with sympathetic neuron-restricted Egr3 ablation have Target Tissue innervation abnormalities similar to mice lacking Egr3 in all Tissues. Microarray analysis performed on sympathetic neurons identified many Target genes deregulated in the absence of Egr3, with some of the most significantly deregulated genes having roles in axonogenesis, dendritogenesis, and axon guidance. Using a novel genetic technique to visualize axons and dendrites in a subpopulation of randomly labeled sympathetic neurons, we found that Egr3 has an essential role in regulating sympathetic neuron dendrite morphology and terminal axon branching, but not in regulating sympathetic axon guidance to their Targets. Together, these results indicate that Egr3 has a sympathetic neuron autonomous role in sympathetic nervous system development that involves modulating downstream Target genes affecting the outgrowth and branching of sympathetic neuron dendrites and axons.
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Egr3 dependent sympathetic Target Tissue innervation in the absence of neuron death.
PloS one, 2011Co-Authors: Laurie C. Eldredge, David H. Quach, Avinash Honasoge, Katherine Gruner, Warren G. TourtellotteAbstract:Nerve Growth Factor (NGF) is a Target Tissue derived neurotrophin required for normal sympathetic neuron survival and Target Tissue innervation. NGF signaling regulates gene expression in sympathetic neurons, which in turn mediates critical aspects of neuron survival, axon extension and terminal axon branching during sympathetic nervous system (SNS) development. Egr3 is a transcription factor regulated by NGF signaling in sympathetic neurons that is essential for normal SNS development. Germline Egr3-deficient mice have physiologic dysautonomia characterized by apoptotic sympathetic neuron death and abnormal innervation to many Target Tissues. The extent to which sympathetic innervation abnormalities in the absence of Egr3 is caused by altered innervation or by neuron death during development is unknown. Using Bax-deficient mice to abrogate apoptotic sympathetic neuron death in vivo, we show that Egr3 has an essential role in Target Tissue innervation in the absence of neuron death. Sympathetic Target Tissue innervation is abnormal in many Target Tissues in the absence of neuron death, and like NGF, Egr3 also appears to effect Target Tissue innervation heterogeneously. In some Tissues, such as heart, spleen, bowel, kidney, pineal gland and the eye, Egr3 is essential for normal innervation, whereas in other Tissues such as lung, stomach, pancreas and liver, Egr3 appears to have little role in innervation. Moreover, in salivary glands and heart, two Tissues where Egr3 has an essential role in sympathetic innervation, NGF and NT-3 are expressed normally in the absence of Egr3 indicating that abnormal Target Tissue innervation is not due to deregulation of these neurotrophins in Target Tissues. Taken together, these results clearly demonstrate a role for Egr3 in mediating sympathetic Target Tissue innervation that is independent of neuron survival or neurotrophin deregulation.
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abnormal sympathetic nervous system development and physiological dysautonomia in egr3 deficient mice
Development, 2008Co-Authors: Laurie C. Eldredge, David H. Quach, Xiaoguang M Gao, Xiaoqiang Han, Jon W Lomasney, Warren G. TourtellotteAbstract:Sympathetic nervous system development depends upon many factors that mediate neuron migration, differentiation and survival. Target Tissue-derived nerve growth factor (NGF) signaling-induced gene expression is required for survival, differentiation and Target Tissue innervation of post-migratory sympathetic neurons. However, the transcriptional regulatory mechanisms mediated by NGF signaling are very poorly defined. Here, we identify Egr3, a member of the early growth response (Egr) family of transcriptional regulators, as having an important role in sympathetic nervous system development. Egr3 is regulated by NGF signaling and it is expressed in sympathetic neurons during development when they depend upon NGF for survival and Target Tissue innervation. Egr3-deficient mice have severe sympathetic Target Tissue innervation abnormalities and profound physiological dysautonomia. Unlike NGF, which is essential for sympathetic neuron survival and for axon branching within Target Tissues, Egr3 is required for normal terminal axon extension and branching, but not for neuron survival. The results indicate that Egr3 is a novel NGF signaling effector that regulates sympathetic neuron gene expression required for normal Target Tissue innervation and function. Egr3-deficient mice have a phenotype that is remarkably similar to humans with sympathetic nervous system disease, raising the possibility that it may have a role in some forms of human dysautonomia, most of which have no known cause.
