And Represses TNF Gene Expression Activating Transcription Factor-2
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Prox1regulates the Subtype-Specific Development of Caudal Ganglionic
The Journal of Neuroscience, September 16, 2015 • 35(37):12869–12889 • 12869 Development/Plasticity/Repair Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons X Goichi Miyoshi,1 Allison Young,1 Timothy Petros,1 Theofanis Karayannis,1 Melissa McKenzie Chang,1 Alfonso Lavado,2 Tomohiko Iwano,3 Miho Nakajima,4 Hiroki Taniguchi,5 Z. Josh Huang,5 XNathaniel Heintz,4 Guillermo Oliver,2 Fumio Matsuzaki,3 Robert P. Machold,1 and Gord Fishell1 1Department of Neuroscience and Physiology, NYU Neuroscience Institute, Smilow Research Center, New York University School of Medicine, New York, New York 10016, 2Department of Genetics & Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, 3Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, 4Laboratory of Molecular Biology, Howard Hughes Medical Institute, GENSAT Project, The Rockefeller University, New York, New York 10065, and 5Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 Neurogliaform (RELNϩ) and bipolar (VIPϩ) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been eluci- dated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP). -
Targeting Endothelial Kruppel-Like Factor 2 (KLF2) in Arteriovenous
Targeting Endothelial Krüppel-like Factor 2 (KLF2) in Arteriovenous Fistula Maturation Failure A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY (Ph.D.) in the Biomedical Engineering Program Department of Biomedical Engineering College of Engineering and Applied Science 2018 by Keith Louis Saum B.S., Wright State University, 2012 Dissertation Committee: Albert Phillip Owens III, Ph.D. (Committee Chair) Begona Campos-Naciff, Ph.D Christy Holland, Ph.D. Daria Narmoneva, Ph.D. Prabir Roy-Chaudhury, M.D., Ph.D Charuhas Thakar, M.D. Abstract The arteriovenous fistula (AVF) is the preferred form of vascular access for hemodialysis. However, 25-60% of AVFs fail to mature to a state suitable for clinical use, resulting in significant morbidity, mortality, and cost for end-stage renal disease (ESRD) patients. AVF maturation failure is recognized to result from changes in local hemodynamics following fistula creation which lead to venous stenosis and thrombosis. In particular, abnormal wall shear stress (WSS) is thought to be a key stimulus which alters endothelial function and promotes AVF failure. In recent years, the transcription factor Krüppel-like factor-2 (KLF2) has emerged as a key regulator of endothelial function, and reduced KLF2 expression has been shown to correlate with disturbed WSS and AVF failure. Given KLF2’s importance in regulating endothelial function, the objective of this dissertation was to investigate how KLF2 expression is regulated by the hemodynamic and uremic stimuli within AVFs and determine if loss of endothelial KLF2 is responsible for impaired endothelial function. -
Global Mef2 Target Gene Analysis in Skeletal and Cardiac Muscle
GLOBAL MEF2 TARGET GENE ANALYSIS IN SKELETAL AND CARDIAC MUSCLE STEPHANIE ELIZABETH WALES A DISSERTATION SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN BIOLOGY YORK UNIVERSITY TORONTO, ONTARIO FEBRUARY 2016 © Stephanie Wales 2016 ABSTRACT A loss of muscle mass or function occurs in many genetic and acquired pathologies such as heart disease, sarcopenia and cachexia which are predominantly found among the rapidly increasing elderly population. Developing effective treatments relies on understanding the genetic networks that control these disease pathways. Transcription factors occupy an essential position as regulators of gene expression. Myocyte enhancer factor 2 (MEF2) is an important transcription factor in striated muscle development in the embryo, skeletal muscle maintenance in the adult and cardiomyocyte survival and hypertrophy in the progression to heart failure. We sought to identify common MEF2 target genes in these two types of striated muscles using chromatin immunoprecipitation and next generation sequencing (ChIP-seq) and transcriptome profiling (RNA-seq). Using a cell culture model of skeletal muscle (C2C12) and primary cardiomyocytes we found 294 common MEF2A binding sites within both cell types. Individually MEF2A was recruited to approximately 2700 and 1600 DNA sequences in skeletal and cardiac muscle, respectively. Two genes were chosen for further study: DUSP6 and Hspb7. DUSP6, an ERK1/2 specific phosphatase, was negatively regulated by MEF2 in a p38MAPK dependent manner in striated muscle. Furthermore siRNA mediated gene silencing showed that MEF2D in particular was responsible for repressing DUSP6 during C2C12 myoblast differentiation. Using a p38 pharmacological inhibitor (SB 203580) we observed that MEF2D must be phosphorylated by p38 to repress DUSP6. -
Cortical Foxp2 Supports Behavioral Flexibility and Developmental Dopamine D1 Receptor Expression
bioRxiv preprint doi: https://doi.org/10.1101/624973; this version posted May 2, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression Marissa Co, Stephanie L. Hickey, Ashwinikumar Kulkarni, Matthew Harper, Genevieve Konopka* Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA *Correspondence: [email protected] Contact information Genevieve Konopka, Ph.D. Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., ND4.300, Dallas, TX 75390-9111 TEL: 214-648-5135, FAX: 214-648-1801, Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/624973; this version posted May 2, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract FoxP2 encodes a forkhead box transcription factor required for the development of neural circuits underlying language, vocalization, and motor-skill learning. Human genetic studies have associated FOXP2 variation with neurodevelopmental disorders (NDDs), and within the cortex, it is coexpressed and interacts with other NDD-associated transcription factors. Cortical Foxp2 is required in mice for proper social interactions, but its role in other NDD-relevant behaviors and molecular pathways is unknown. -
Foxp2 Loss of Function Increases Striatal Direct Pathway Inhibition Via Increased GABA Release
Brain Structure and Function https://doi.org/10.1007/s00429-018-1746-6 ORIGINAL ARTICLE Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release Jon‑Ruben van Rhijn1,2,3 · Simon E. Fisher3,4 · Sonja C. Vernes2,4 · Nael Nadif Kasri1,5 Received: 8 March 2018 / Accepted: 31 August 2018 © The Author(s) 2018 Abstract Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/ inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-medi- ated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive. Keywords Foxp2 · Excitatory-inhibitory balance · Neurodevelopment · D1R-MSN · Striatum Introduction Balanced neuronal activity between cortex, striatum and Sonja C. Vernes and Nael Nadif Kasri contributed equally to this thalamus is essential for the generation of voluntary move- work. ments (Shepherd 2013). Imbalanced activity within the stria- tum is known to disrupt complex motor behaviors, such as Electronic supplementary material The online version of this the production of spoken language (Peach 2004; Square- article (https ://doi.org/10.1007/s0042 9-018-1746-6) contains supplementary material, which is available to authorized users. -
Transcription Factor MEF2C Influences Neural Stem/Progenitor Cell Differentiation and Maturation in Vivo
Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo Hao Li*†, Jonathan C. Radford*†, Michael J. Ragusa‡, Katherine L. Shea‡, Scott R. McKercher*, Jeffrey D. Zaremba*, Walid Soussou*, Zhiguo Nie*, Yeon-Joo Kang*, Nobuki Nakanishi*, Shu-ichi Okamoto*, Amanda J. Roberts§, John J. Schwarz‡, and Stuart A. Lipton*§¶ *Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, CA 92037; ‡Center for Cardiovascular Sciences, Albany Medical Center, Albany, NY 12208; and §Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037 Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved May 3, 2008 (received for review March 21, 2008) Emerging evidence suggests that myocyte enhancer factor 2 (MEF2) (7). Therefore, to investigate the role of MEF2C in brain develop- transcription factors act as effectors of neurogenesis in the brain, with ment, we conditionally knocked out Mef2c in neural stem/ MEF2C the predominant isoform in developing cerebrocortex. Here, progenitor cells by E9.5 by using a nestin-driven Cre [see supporting we show that conditional knockout of Mef2c in nestin-expressing information (SI) Materials and Methods) (11). Heterozygous neural stem/progenitor cells (NSCs) impaired neuronal differentiation n-Creϩ/Mef2cloxp/ϩ mice were indistinguishable from wild type in vivo, resulting in aberrant compaction and smaller somal size. NSC (WT) and served as littermate controls. Evidence for Cre-mediated proliferation and survival were not affected. Conditional null mice recombination included PCR, immunofluorescence, and immuno- surviving to adulthood manifested more immature electrophysiolog- blotting. Normally, MEF2 activity (Fig. -
A Mef2 Gene That Generates a Muscle-Specific Isoform Via Alternative Mrna Splicing JAMES F
MOLECULAR AND CELLULAR BIOLOGY, Mar. 1994, p. 1647-1656 Vol. 14, No. 3 0270-7306/94/$04.00 + 0 Copyright C) 1994, American Society for Microbiology A Mef2 Gene That Generates a Muscle-Specific Isoform via Alternative mRNA Splicing JAMES F. MARTIN,' JOSEPH M. MIANO,' CAROLYN M. HUSTAD,2 NEAL G. COPELAND,2 NANCY A. JENKINS,2 AND ERIC N. OLSON'* Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,1 and Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 217022 Received 21 July 1993/Returned for modification 30 September 1993/Accepted 2 December 1993 Members of the myocyte-specific enhancer-binding factor 2 (MEF2) family of transcription factors bind a conserved A/T-rich sequence in the control regions of numerous muscle-specific genes. Mammalian MEF2 proteins have been shown previously to be encoded by three genes, MeQt, xMeJ2, and Me.2c, each of which gives rise to multiple alternatively spliced transcripts. We describe the cloning of a new member of the MEF2 family from mice, termed MEF2D, which shares extensive homology with other MEF2 proteins but is the product of a separate gene. MEF2D binds to and activates transcription through the MEF2 site and forms heterodimers with other members of the MEF2 family. Deletion mutations show that the carboxyl terminus of MEF2D is required for efficient transactivation. MEF2D transcripts are widely expressed, but alternative splicing of MEF2D transcripts gives rise to a muscle-specific isoform which is induced during myoblast differentiation. -
Rb and N-Ras Function Together to Control Differentiation in the Mouse
Rb and N-ras Function Together to Control Differentiation in the Mouse The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Takahashi, C., R. T. Bronson, M. Socolovsky, B. Contreras, K. Y. Lee, T. Jacks, M. Noda, R. Kucherlapati, and M. E. Ewen. 2003. “Rb and N-Ras Function Together To Control Differentiation in the Mouse.” Molecular and Cellular Biology 23 (15): 5256–68. doi:10.1128/ MCB.23.15.5256-5268.2003. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41543053 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA MOLECULAR AND CELLULAR BIOLOGY, Aug. 2003, p. 5256–5268 Vol. 23, No. 15 0270-7306/03/$08.00ϩ0 DOI: 10.1128/MCB.23.15.5256–5268.2003 Copyright © 2003, American Society for Microbiology. All Rights Reserved. Rb and N-ras Function Together To Control Differentiation in the Mouse Chiaki Takahashi,1† Roderick T. Bronson,2,3 Merav Socolovsky,4 Bernardo Contreras,1 Kwang Youl Lee,1‡ Tyler Jacks,5 Makoto Noda,6 Raju Kucherlapati,7 and Mark E. Ewen1* Department of Medical Oncology and Medicine, Dana-Farber Cancer Institute and Harvard Medical School,1 and Rodent Histopathology Core3 and Harvard-Partners Center for Genetics and Genomics,7 Harvard Medical School, Boston, Massachusetts 02115; Department of Pathology, Tufts University Schools -
Integrative Analysis Identifies Bhlh Transcription Factors As Contributors to Parkinson's Disease Risk Mechanisms
www.nature.com/scientificreports OPEN Integrative analysis identifes bHLH transcription factors as contributors to Parkinson’s disease risk mechanisms Victoria Berge‑Seidl1,2, Lasse Pihlstrøm 1 & Mathias Toft 1,2* Genome‑wide association studies (GWAS) have identifed multiple genetic risk signals for Parkinson’s disease (PD), however translation into underlying biological mechanisms remains scarce. Genomic functional annotations of neurons provide new resources that may be integrated into analyses of GWAS fndings. Altered transcription factor binding plays an important role in human diseases. Insight into transcriptional networks involved in PD risk mechanisms may thus improve our understanding of pathogenesis. We analysed overlap between genome‑wide association signals in PD and open chromatin in neurons across multiple brain regions, fnding a signifcant enrichment in the superior temporal cortex. The involvement of transcriptional networks was explored in neurons of the superior temporal cortex based on the location of candidate transcription factor motifs identifed by two de novo motif discovery methods. Analyses were performed in parallel, both fnding that PD risk variants signifcantly overlap with open chromatin regions harboring motifs of basic Helix‑Loop‑Helix (bHLH) transcription factors. Our fndings show that cortical neurons are likely mediators of genetic risk for PD. The concentration of PD risk variants at sites of open chromatin targeted by members of the bHLH transcription factor family points to an involvement of these transcriptional networks in PD risk mechanisms. Parkinson’s disease (PD) is a progressive neurodegenerative disorder afecting about 1% of the population above 60 years of age1. Te cause of neuronal death is poorly understood, and this is obstructing the path toward more efective treatments. -
Glucocorticoid Receptor and Myocyte Enhancer Factor 2 Cooperate to Regulate the Expression of C-JUN in a Neuronal Context
J Mol Neurosci (2012) 48:209–218 DOI 10.1007/s12031-012-9809-2 Glucocorticoid Receptor and Myocyte Enhancer Factor 2 Cooperate to Regulate the Expression of c-JUN in a Neuronal Context Niels Speksnijder & Kenneth V. Christensen & Michael Didriksen & E. Ronald De Kloet & Nicole A. Datson Received: 17 April 2012 /Accepted: 7 May 2012 /Published online: 24 May 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com Abstract The glucocorticoid receptor (GR) and myocyte c-JUN. In conclusion, for the first time, we show that enhancer factor 2 (MEF2) are transcription factors involved activated GR requires MEF2 to regulate c-JUN. At the in neuronal plasticity. c-JUN, a target gene of GR and same time, GR influences MEF2 activity and DNA binding. MEF2, plays a role in regulating both synaptic strength These results give novel insight into the molecular interplay of and synapse number. The aim of this study was to investi- GR and MEF2 in the control of genes important for neuronal gate the nature of this dual regulation of c-JUN by GR and plasticity. MEF2 in a neuronal context. First, we showed that GR mediates the dexamethasone-induced suppression of c- Keywords Glucocorticoid receptor . Myocyte enhancer JUN mRNA expression. Next, we observed that GR activa- factor 2 . c-JUN . Dexamethasone . PC-12 cells tion resulted in an increase in phosphorylation of MEF2, a post-translational modification known to change MEF2 Abbreviations from a transcriptional enhancer to a repressor. In addition, CDK5 Cyclin-dependent kinase 5 we observed an enhanced binding of MEF2 to genomic sites ChIP Chromatin immuno-precipitation directly upstream of the c-JUN gene upon GR activation. -
Foxp2 Regulates Anatomical Features That May Be Relevant for Vocal Behaviors and Bipedal Locomotion
Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion Shuqin Xua, Pei Liua, Yuanxing Chena, Yi Chenb, Wei Zhanga, Haixia Zhaoa, Yiwei Caoa, Fuhua Wanga, Nana Jianga, Shifeng Lina, Baojie Lia, Zhenlin Zhangc, Zhanying Weic, Ying Fanc, Yunyun Jind, Lin Hea, Rujiang Zhoua, Joseph D. Dekkere, Haley O. Tuckere, Simon E. Fisherf,g, Zhengju Yaoa, Quansheng Liub,1, Xuechun Xiaa,1, and Xizhi Guoa,1 aBio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200240 Shanghai, China; bGuangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Guangdong Institute of Applied Biological Resources, 510260 Guangzhou, China; cThe Sixth People’s Hospital of Shanghai, School of Medicine, Shanghai Jiao Tong University, 200240 Shanghai, China; dInstitute of Biomedical Sciences and School of Life Sciences, East China Normal University, 200241 Shanghai, China; eInstitute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712; fLanguage and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands; and gDonders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 HE, The Netherlands Edited by Joseph S. Takahashi, Howard Hughes Medical Institute and University of Texas Southwestern Medical Center, Dallas, TX, and approved July 12, 2018 (received for review December 18, 2017) Fundamental human traits, such as language and bipedalism, are on the lineage that led to modern humans (24, 25). Two amino associated with a range of anatomical adaptations in craniofacial acid substitutions occurred in human FOXP2 after splitting from shaping and skeletal remodeling. -
Research Article ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy
Hindawi Publishing Corporation Journal of Ophthalmology Volume 2010, Article ID 465824, 11 pages doi:10.1155/2010/465824 Research Article ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy Yuexiu Wu, Yufeng Zuo, Rana Chakrabarti, Biao Feng, Shali Chen, and Subrata Chakrabarti Department of Pathology, Schulich School of Medicine, University of Western Ontario, London, ON, Canada N6A 5A5 Correspondence should be addressed to Subrata Chakrabarti, [email protected] Received 15 December 2009; Revised 15 April 2010; Accepted 19 May 2010 Academic Editor: Susanne Mohr Copyright © 2010 Yuexiu Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Diabetic retinopathy is one of the most common causes of blindness in North America. Several signaling mechanisms are activated secondary to hyperglycemia in diabetes, leading to activation of vasoactive factors. We investigated a novel pathway, namely extracellular signal regulated kinase 5 (ERK5) mediated signaling, in modulating glucose-induced vascular endothelial growth factor (VEGF) expression. Human microvascular endothelial cells (HMVEC) were exposed to glucose. In parallel, retinal tissues from streptozotocin-induced diabetic rats were examined after 4 months of follow-up. In HMVECs, glucose caused initial activation followed by deactivation of ERK5 and its downstream mediators myocyte enhancing factor 2C (MEF2C) and Kruppel- like factor 2 (KLF2) mRNA expression. ERK5 inactivation further led to augmented VEGF mRNA expression. Furthermore, siRNA mediated ERK5 gene knockdown suppressed MEF2C and KLF2 expression and increased VEGF expression and angiogenesis. On the other hand, constitutively active MEK5, an activator of ERK5, increased ERK5 activation and ERK5 and KLF2 mRNA expression and attenuated basal- and glucose-induced VEGF mRNA expression.