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Article ; Online: A novel Oprm1-Cre mouse maintains endogenous expression, function and enables detailed molecular characterization of μ-opioid receptor cells.

Juliet Mengaziol / Amelia D Dunn / Gregory Salimando / Lisa Wooldridge / Jordi Crues-Muncunill / Darrell Eacret / Chongguang Chen / Kathryn Bland / Lee-Yuan Liu-Chen / Michelle E Ehrlich / Gregory Corder / Julie A Blendy

PLoS ONE, Vol 17, Iss 12, p e

2022 Volume 0270317

Abstract: Key targets of both the therapeutic and abused properties of opioids are μ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the ... ...

Abstract	Key targets of both the therapeutic and abused properties of opioids are μ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the cellular mechanisms underlying opioid addiction. Given that addictive opioids such as morphine, oxycodone, heroin, and fentanyl all activate MORs, and current therapies such as naloxone and buprenorphine block this activation, the availability of tools to mechanistically investigate opioid-mediated cellular and behavioral phenotypes are necessary. Therefore, we derived, validated, and applied a novel MOR-specific Cre mouse line, inserting a T2A cleavable peptide sequence and the Cre coding sequence into the MOR 3'UTR. Importantly, this line shows specificity and fidelity of MOR expression throughout the brain and with respect to function, there were no differences in behavioral responses to morphine when compared to wild type mice, nor are there any alterations in Oprm1 gene expression or receptor density. To assess Cre recombinase activity, MOR-Cre mice were crossed with the floxed GFP-reporters, RosaLSLSun1-sfGFP or RosaLSL-GFP-L10a. The latter allowed for cell type specific RNA sequencing via TRAP (Translating Ribosome Affinity Purification) of striatal MOR+ neurons following opioid withdrawal. The breadth of utility of this new tool will greatly facilitate the study of opioid biology under varying conditions.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females

Allen L. Pan / Mickael Audrain / Emmy Sakakibara / Rajeev Joshi / Xiaodong Zhu / Qian Wang / Minghui Wang / Noam D. Beckmann / Eric E. Schadt / Sam Gandy / Bin Zhang / Michelle E. Ehrlich / Stephen R. Salton

Cells, Vol 11, Iss 3880, p

2022 Volume 3880

Abstract: Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer’s disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity ... ...

Abstract	Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer’s disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 ( DUSP4 ) [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, DUSP4 gene expression, like that of VGF , is downregulated in postmortem Alzheimer’s disease (AD) brains. We investigated the roles that this VGF / DUSP4 network plays in the development of learning behavior impairment and neuropathology in the 5xFAD amyloidopathy mouse model. We found reductions in DUSP4 expression in the hippocampi of male AD subjects, correlating with increased CDR scores, and in 4-month-old female and 12–18-month-old male 5xFAD hippocampi. Adeno-associated virus (AAV5)-mediated overexpression of DUSP4 in 5xFAD mouse dorsal hippocampi (dHc) rescued impaired Barnes maze performance in females but not in males, while amyloid loads were reduced in both females and males. Bulk RNA sequencing of the dHc from 5-month-old mice overexpressing DUSP4, and Ingenuity Pathway and Enrichr analyses of differentially expressed genes (DEGs), revealed that DUSP4 reduced gene expression in female 5xFAD mice in neuroinflammatory, interferon-gamma (IFNγ), programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-1), and extracellular signal-regulated kinase (ERK)/MAPK pathways, via which DUSP4 may modulate AD phenotype with gender-specificity.
Keywords	Alzheimer’s disease ; dual-specificity protein phosphatase 4 ; disease-associated microglia ; mitogen-activated protein kinase ; neuroinflammation ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons

Mads E. Hauberg / Jordi Creus-Muncunill / Jaroslav Bendl / Alexey Kozlenkov / Biao Zeng / Chuhyon Corwin / Sarah Chowdhury / Harald Kranz / Yasmin L. Hurd / Michael Wegner / Anders D. Børglum / Stella Dracheva / Michelle E. Ehrlich / John F. Fullard / Panos Roussos

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 16

Abstract: Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological ... ...

Abstract	Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits.
Keywords	Science ; Q
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Common schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 16

Abstract	Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits.
Keywords	Science ; Q
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Unbiased identification of novel transcription factors in striatal compartmentation and striosome maturation

Maria-Daniela Cirnaru / Sicheng Song / Kizito-Tshitoko Tshilenge / Chuhyon Corwin / Justyna Mleczko / Carlos Galicia Aguirre / Houda Benlhabib / Jaroslav Bendl / Pasha Apontes / John Fullard / Jordi Creus-Muncunill / Azadeh Reyahi / Ali M Nik / Peter Carlsson / Panos Roussos / Sean D Mooney / Lisa M Ellerby / Michelle E Ehrlich

eLife, Vol

2021 Volume 10

Abstract: Many diseases are linked to dysregulation of the striatum. Striatal function depends on neuronal compartmentation into striosomes and matrix. Striatal projection neurons are GABAergic medium spiny neurons (MSNs), subtyped by selective expression of ... ...

Abstract	Many diseases are linked to dysregulation of the striatum. Striatal function depends on neuronal compartmentation into striosomes and matrix. Striatal projection neurons are GABAergic medium spiny neurons (MSNs), subtyped by selective expression of receptors, neuropeptides, and other gene families. Neurogenesis of the striosome and matrix occurs in separate waves, but the factors regulating compartmentation and neuronal differentiation are largely unidentified. We performed RNA- and ATAC-seq on sorted striosome and matrix cells at postnatal day 3, using the Nr4a1-EGFP striosome reporter mouse. Focusing on the striosome, we validated the localization and/or role of Irx1, Foxf2, Olig2, and Stat1/2 in the developing striosome and the in vivo enhancer function of a striosome-specific open chromatin region 4.4 Kb downstream of Olig2. These data provide novel tools to dissect and manipulate the networks regulating MSN compartmentation and differentiation, including in human iPSC-derived striatal neurons for disease modeling and drug discovery.
Keywords	Striosome ; Olig2 ; striatum ; Nr4a1 ; Foxf2 ; transcription factors ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Induction of DARPP-32 by brain-derived neurotrophic factor in striatal neurons in vitro is modified by histone deacetylase inhibitors and Nab2.

Samira Chandwani / Serene Keilani / Maitane Ortiz-Virumbrales / Andrika Morant / Steve Bezdecny / Michelle E Ehrlich

PLoS ONE, Vol 8, Iss 10, p e

2013 Volume 76842

Abstract: Neurotrophins and modifiers of chromatin acetylation and deacetylation participate in regulation of transcription during neuronal maturation and maintenance. The striatal medium spiny neuron is supported by cortically-derived brain derived neurotrophic ... ...

Abstract	Neurotrophins and modifiers of chromatin acetylation and deacetylation participate in regulation of transcription during neuronal maturation and maintenance. The striatal medium spiny neuron is supported by cortically-derived brain derived neurotrophic factor and is the most vulnerable neuron in Huntington's disease, in which growth factor and histone deacetylase activity are both disrupted. We examined the ability of three histone deacetylase inhibitors, trichostatin A, valproic acid and Compound 4 b, alone and combined with brain derived neurotrophic factor (BDNF), to promote phenotypic maturation of striatal medium spiny neurons in vitro. Exposure of these neurons to each of the three compounds led to an increase in overall histone H3 and H4 acetylation, dopamine and cyclic AMP-regulated phosphoprotein, 32 kDa (DARPP-32) mRNA and protein, and mRNA levels of other markers of medium spiny neuron maturation. We were, however, unable to prove that HDAC inhibitors directly lead to remodeling of Ppp1r1b chromatin. In addition, induction of DARPP-32 by brain-derived neurotrophic factor was inhibited by histone deacetylase inhibitors. Although BDNF-induced increases in pTrkB, pAkt, pERK and Egr-1 were unchanged by combined application with VPA, the increase in DARPP-32 was relatively diminished. Strikingly, the NGF1A-binding protein, Nab2, was induced by BDNF, but not in the presence of VPA or TSA. Gel shift analysis showed that α-Nab2 super-shifted a band that is more prominent with extract derived from BDNF-treated neurons than with extracts from cultures treated with VPA alone or VPA plus BDNF. In addition, overexpression of Nab2 induced DARPP-32. We conclude that histone deacetylase inhibitors inhibit the induction of Nab2 by BDNF, and thereby the relative induction of DARPP-32.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Integrated biology approach reveals molecular and pathological interactions among Alzheimer’s Aβ42, Tau, TREM2, and TYROBP in Drosophila models

Michiko Sekiya / Minghui Wang / Naoki Fujisaki / Yasufumi Sakakibara / Xiuming Quan / Michelle E. Ehrlich / Philip L. De Jager / David A. Bennett / Eric E. Schadt / Sam Gandy / Kanae Ando / Bin Zhang / Koichi M. Iijima

Genome Medicine, Vol 10, Iss 1, Pp 1-

2018 Volume 20

Abstract: Abstract Background Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer’s disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed ... ...

Abstract	Abstract Background Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer’s disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP. Methods In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts. Results Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD. Conclusions The comprehensive pathological and molecular data generated through this study strongly validate the causal role of TREM2/TYROBP in driving molecular networks in AD and AD-related phenotypes in flies.
Keywords	Alzheimer’s disease ; Amyloid-β (Aβ) peptides ; Microtubule-associated protein tau ; TYROBP (tyrosine kinase binding protein) ; TREM2 (triggering receptor expressed on myeloid cells 2) ; Differential expression ; Medicine ; R ; Genetics ; QH426-470
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: THAP1

Francesca Aguilo / Zuchra Zakirova / Katie Nolan / Ryan Wagner / Rajal Sharma / Megan Hogan / Chengguo Wei / Yifei Sun / Martin J. Walsh / Kevin Kelley / Weijia Zhang / Laurie J. Ozelius / Pedro Gonzalez-Alegre / Thomas P. Zwaka / Michelle E. Ehrlich

Stem Cell Reports, Vol 9, Iss 1, Pp 92-

Role in Mouse Embryonic Stem Cell Survival and Differentiation

2017 Volume 107

Abstract: THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 ... ...

Abstract	THAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression.
Keywords	Thanatos-associated protein domain-containing apoptosis-associated protein 1 ; THAP1 ; dystonia ; differentiation ; survival ; embryonic stem cells ; transcriptomics ; neuroectodermal differentiation ; apoptosis ; zinc finger transcription factor ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2017-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK.

Steve Pedrini / Troy L Carter / George Prendergast / Suzana Petanceska / Michelle E Ehrlich / Sam Gandy

PLoS Medicine, Vol 2, Iss 1, p e

2005 Volume 18

Abstract: Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, ... ...

Abstract	Statins are widely used cholesterol-lowering drugs that act by inhibiting HMGCoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Recent evidence suggests that statin use may be associated with a decreased risk for Alzheimer disease, although the mechanisms underlying this apparent risk reduction are poorly understood. One popular hypothesis for statin action is related to the drugs' ability to activate alpha-secretase-type shedding of the alpha-secretase-cleaved soluble Alzheimer amyloid precursor protein ectodomain (sAPP(alpha)). Statins also inhibit the isoprenoid pathway, thereby modulating the activities of the Rho family of small GTPases-Rho A, B, and C-as well as the activities of Rac and cdc42. Rho proteins, in turn, exert many of their effects via Rho-associated protein kinases (ROCKs). Several cell-surface molecules are substrates for activated alpha-secretase-type ectodomain shedding, and regulation of shedding typically occurs via activation of protein kinase C or extracellular-signal-regulated protein kinases, or via inactivation of protein phosphatase 1 or 2A. However, the possibility that these enzymes play a role in statin-stimulated shedding has been excluded, leading us to investigate whether the Rho/ROCK1 protein phosphorylation pathway might be involved.We found that both atorvastatin and simvastatin stimulated sAPP(alpha) shedding from a neuroblastoma cell line via a subcellular mechanism apparently located upstream of endocytosis. A farnesyl transferase inhibitor also increased sAPP(alpha) shedding, as did a dominant negative form of ROCK1. Most conclusively, a constitutively active ROCK1 molecule inhibited statin-stimulated sAPP(alpha) shedding.Together, these data suggest that statins exert their effects on shedding of sAPP(alpha) from cultured cells, at least in part, by modulation of the isoprenoid pathway and ROCK1.
Keywords	Medicine ; R
Subject code	571
Language	English
Publishing date	2005-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Stable G protein-effector complexes in striatal neurons

Keqiang Xie / Ikuo Masuho / Chien-Cheng Shih / Yan Cao / Keita Sasaki / Chun Wan J Lai / Pyung-Lim Han / Hiroshi Ueda / Carmen W Dessauer / Michelle E Ehrlich / Baoji Xu / Barry M Willardson / Kirill A Martemyanov

eLife, Vol

mechanism of assembly and role in neurotransmitter signaling

2015 Volume 4

Abstract: In the striatum, signaling via G protein-coupled neurotransmitter receptors is essential for motor control. Critical to this process is the effector enzyme adenylyl cyclase type 5 (AC5) that produces second messenger cAMP upon receptor-mediated ... ...

Abstract	In the striatum, signaling via G protein-coupled neurotransmitter receptors is essential for motor control. Critical to this process is the effector enzyme adenylyl cyclase type 5 (AC5) that produces second messenger cAMP upon receptor-mediated activation by G protein Golf. However, the molecular organization of the Golf-AC5 signaling axis is not well understood. In this study, we report that in the striatum AC5 exists in a stable pre-coupled complex with subunits of Golf heterotrimer. We use genetic mouse models with disruption in individual components of the complex to reveal hierarchical order of interactions required for AC5-Golf stability. We further identify that the assembly of AC5-Golf complex is mediated by PhLP1 chaperone that plays central role in neurotransmitter receptor coupling to cAMP production motor learning. These findings provide evidence for the existence of stable G protein-effector signaling complexes and identify a new component essential for their assembly.
Keywords	G protein ; signal transduction ; striatum ; cAMP ; motor control ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2015-11-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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