Life Sciences Commons^™

Differential Effects Of Rasa3 Mutations On Hematopoiesis Are Profoundly Influenced By Genetic Background And Molecular Variant., Ray F. Robledo, Steven L. Ciciotte, Joel H Graber, Yue Zhao, Amy J Lambert, Babette Gwynn, Nathaniel J Maki, Elena C Brindley, Emily Hartman, Lionel Blanc, Luanne L. Peters

Faculty Research 2020

Studies of the severely pancytopenic scat mouse model first demonstrated the crucial role of RASA3, a dual RAS and RAP GTPase activating protein (GAP), in hematopoiesis. RASA3 is required for survival in utero; germline deletion is lethal at E12.5-13.5 due to severe hemorrhage. Here, conditional deletion in hematopoietic stem and progenitor cells (HSPCs) using Vav-iCre recapitulates the null phenotype demonstrating that RASA3 is required at the stem and progenitor level to maintain blood vessel development and integrity and effective blood production. In adults, bone marrow blood cell production and spleen stress erythropoiesis are suppressed significantly upon induction of RASA3 deficiency, …

Mouse Mutant Phenotyping At Scale Reveals Novel Genes Controlling Bone Mineral Density., Anna L Swan, Christine Schütt, Jan Rozman, Maria Del Mar Muñiz Moreno, Stefan Brandmaier, Michelle Simon, Stefanie Leuchtenberger, Mark Griffiths, Robert Brommage, Piia Keskivali-Bond, Harald Grallert, Thomas Werner, Raffaele Teperino, Lore Becker, Gregor Miller, Ala Moshiri, John R Seavitt, Derek D Cissell, Terrence F Meehan, Elif F Acar, Christopher J Lelliott, Ann M Flenniken, Marie-France Champy, Tania Sorg, Abdel Ayadi, Robert E Braun, Heather Cater, Mary E Dickinson, Paul Flicek, Juan Gallegos, Elena J Ghirardello, Jason D Heaney, Sylvie Jacquot, Connor Lally, John G Logan, Lydia Teboul, Jeremy Mason, Nadine Spielmann, Colin Mckerlie, Stephen A. Murray, Lauryl M J Nutter, Kristian F Odfalk, Helen Parkinson, Jan Prochazka, Corey L Reynolds, Mohammed Selloum, Frantisek Spoutil, Karen L. Svenson, Taylor S Vales, Sara E Wells, Jacqueline K White, Radislav Sedlacek, Wolfgang Wurst, Kent K C Lloyd, Peter I Croucher, Helmut Fuchs, Graham R Williams, Duncan Bassett, Valerie Gailus-Durner, Yann Herault, Ann-Marie Mallon, Steve D M Brown, Philipp Mayer-Kuckuk, Martin Hrabe De Angelis, Impc Consortium

Faculty Research 2020

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored …

A Drosophila Screen Identifies Nkcc1 As A Modifier Of Ngly1 Deficiency, Dana M Talsness, Katie G Owings, Emily Coelho, Gaelle Mercenne, John M Pleinis, Raghavendran Partha, Kevin A Hope, Aamir Zuberi, Nathan L Clark, Cathleen Lutz, Aylin R Rodan, Clement Y Chow

Faculty Research 2020

N-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0 to 100% lethality. Association analysis on the lethality phenotype, as well as an evolutionary rate covariation analysis, generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2 …

Toll-Like Receptor 7 Is Required For Lacrimal Gland Autoimmunity And Type 1 Diabetes Development In Male Nonobese Diabetic Mice., Ivy L Debreceni, Michael S Chimenti, David V. Serreze, Aron M Geurts, Yi-Guang Chen, Scott M Lieberman

Faculty Research 2020

Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 …

The Involvement Of Neuroimmune Cells In Adipose Innervation., Magdalena Blaszkiewicz, Elizabeth Wood, Sigi Koizar, Jake Willows, Ryan Anderson, Yu-Hua Tseng, James W Godwin, Kristy L Townsend

Faculty Research 2020

BACKGROUND: Innervation of adipose tissue is essential for the proper function of this critical metabolic organ. Numerous surgical and chemical denervation studies have demonstrated how maintenance of brain-adipose communication through both sympathetic efferent and sensory afferent nerves helps regulate adipocyte size, cell number, lipolysis, and 'browning' of white adipose tissue. Neurotrophic factors are growth factors that promote neuron survival, regeneration, and plasticity, including neurite outgrowth and synapse formation. Peripheral immune cells have been shown to be a source of neurotrophic factors in humans and mice. Although a number of immune cells reside in the adipose stromal vascular fraction (SVF), it …

Prd-2 Directly Regulates Casein Kinase I And Counteracts Nonsense-Mediated Decay In The Neurospora Circadian Clock., Christina M Kelliher, Randy Lambreghts, Qijun Xiang, Christopher L. Baker, Jennifer J Loros, Jay C Dunlap

Faculty Research 2020

No abstract provided.

Health Benefits Attributed To 17Α-Estradiol, A Lifespan-Extending Compound, Are Mediated Through Estrogen Receptor Α., Shivani N Mann, Niran Hadad, Molly Nelson Holte, Alicia R Rothman, Roshini Sathiaseelan, Samim Ali Mondal, Martin-Paul Agbaga, Archana Unnikrishnan, Malayannan Subramaniam, John Hawse, Derek M Huffman, Willard M Freeman, Michael B Stout

Faculty Research 2020

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and …

C11orf95-Rela Reprograms 3d Epigenome In Supratentorial Ependymoma., Jacqueline Jufen Zhu, Nathaniel L. Jillette, Xiao-Nan Li, Albert Cheng, Ching C Lau

Faculty Research 2020

Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451-455 (2014); Pietsch et al. Acta Neuropathol 127:609-611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional …

Investigation Of Covid-19 Comorbidities Reveals Genes And Pathways Coincident With The Sars-Cov-2 Viral Disease., Mary E. Dolan, David P. Hill, Gaurab Mukherjee, Monica Mcandrews, Elissa J Chesler, Judith A. Blake

Faculty Research 2020

The emergence of the SARS-CoV-2 virus and subsequent COVID-19 pandemic initiated intense research into the mechanisms of action for this virus. It was quickly noted that COVID-19 presents more seriously in conjunction with other human disease conditions such as hypertension, diabetes, and lung diseases. We conducted a bioinformatics analysis of COVID-19 comorbidity-associated gene sets, identifying genes and pathways shared among the comorbidities, and evaluated current knowledge about these genes and pathways as related to current information about SARS-CoV-2 infection. We performed our analysis using GeneWeaver (GW), Reactome, and several biomedical ontologies to represent and compare common COVID-19 comorbidities. Phenotypic analysis …

Model Organism Development And Evaluation For Late-Onset Alzheimer's Disease: Model-Ad., Adrian L Oblak, Stefania Forner, Paul R Territo, Michael Sasner, Gregory W. Carter, Gareth R Howell, Stacey J Sukoff-Rizzo, Benjamin A Logsdon, Lara M Mangravite, Ali Mortazavi, David Baglietto-Vargas, Kim N Green, Grant R Macgregor, Marcelo A Wood, Andrea J Tenner, Frank M Laferla, Bruce T Lamb, The Model-Ad Consortium

Faculty Research 2020

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease-modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late-onset …

Complement Peptide C3a Receptor 1 Promotes Optic Nerve Degeneration In Dba/2j Mice., Jeffrey M. Harder, Pete A. Williams, Catherine E. Braine, Hongyuan Yang, Jocelyn M Thomas, Nicole E Foxworth, Simon W M John, Gareth R Howell

Faculty Research 2020

BACKGROUND: The risk of glaucoma increases significantly with age and exposure to elevated intraocular pressure, two factors linked with neuroinflammation. The complement cascade is a complex immune process with many bioactive end-products, including mediators of inflammation. Complement cascade activation has been shown in glaucoma patients and models of glaucoma. However, the function of complement-mediated inflammation in glaucoma is largely untested. Here, the complement peptide C3a receptor 1 was genetically disrupted in DBA/2J mice, an ocular hypertensive model of glaucoma, to test its contribution to neurodegeneration.

METHODS: A null allele of C3ar1 was backcrossed into DBA/2J mice. Development of iris disease, …

A Novel Systems Biology Approach To Evaluate Mouse Models Of Late-Onset Alzheimer's Disease., Christoph Preuss, Ravi S Pandey, Erin Piazza, Alexander D Fine, Asli Uyar, Thanneer Perumal, Dylan Garceau, Kevin P Kotredes, Harriet M. Williams, Lara M Mangravite, Bruce T Lamb, Adrian L Oblak, Gareth R Howell, Michael Sasner, Benjamin A Logsdon, Model-Ad Consortium, Gregory W. Carter

Faculty Research 2020

BACKGROUND: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer's have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes.

RESULTS: This resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString …

Canagliflozin Extends Life Span In Genetically Heterogeneous Male But Not Female Mice., Richard A Miller, David E Harrison, David B Allison, Molly A. Bogue, Lucas Debarba, Vivian Diaz, Elizabeth Fernandez, Andrzej Galecki, W Timothy Garvey, Hashan Jayarathne, Navasuja Kumar, Martin A Javors, Warren C Ladiges, Francesca Macchiarini, James Nelson, Peter C. Reifsnyder, Nadia Rosenthal, Marianna Sadagurski, Adam B Salmon, Daniel L Smith, Jessica M Snyder, David B Lombard, Randy Strong

Faculty Research 2020

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology …

Rapamycin-Mediated Mouse Lifespan Extension: Late-Life Dosage Regimes With Sex-Specific Effects., Randy Strong, Richard A Miller, Molly A. Bogue, Elizabeth Fernandez, Martin A Javors, Sergiy Libert, Paul Anthony Marinez, Michael P Murphy, Nicolas Musi, James F Nelson, Michael Petrascheck, Peter C. Reifsnyder, Arlan Richardson, Adam B Salmon, Francesca Macchiarini, David E Harrison

Faculty Research 2020

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more …

Reduced Gabaergic Neuron Excitability, Altered Synaptic Connectivity, And Seizures In A Kcnt1 Gain-Of-Function Mouse Model Of Childhood Epilepsy., Amy N Shore, Sophie Colombo, William F Tobin, Sabrina Petri, Erin R Cullen, Soledad Dominguez, Christopher D Bostick, Michael A Beaumont, Damian Williams, Dion Khodagholy, Mu Yang, Cathleen M Lutz, Yueqing Peng, Jennifer N Gelinas, David B Goldstein, Michael J Boland, Wayne N Frankel, Matthew C Weston

Faculty Research 2020

Gain-of-function (GOF) variants in K⁺ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K⁺ currents lead to network hyperexcitability. Here, we introduce a human Na⁺-activated K⁺ (K_Na) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases K_Na currents in cortical excitatory and inhibitory neurons, there is an increase in the K_Na current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, …

Genetic Differences And Longevity-Related Phenotypes Influence Lifespan And Lifespan Variation In A Sex-Specific Manner In Mice., Rong Yuan, C J M Musters, Yun Zhu, Tracy R Evans, Yujie Sun, Elissa J Chesler, Luanne L. Peters, David E Harrison, Andrzej Bartke

Faculty Research 2020

Epidemiological studies of human longevity found two interesting features, robust advantage of female lifespan and consistent reduction of lifespan variation. To help understand the genetic aspects of these phenomena, the current study examined sex differences and variation of longevity using previously published mouse data sets including data on lifespan, age of puberty, and circulating insulin-like growth factor 1 (IGF1) levels in 31 inbred strains, data from colonies of nuclear-receptor-interacting protein 1 (Nrip1) knockout mice, and a congenic strain, B6.C3H-Igf1. Looking at the overall data for all inbred strains, the results show no significant difference in lifespan and lifespan variation between …

Gli3 Utilizes Hand2 To Synergistically Regulate Tissue-Specific Transcriptional Networks., Kelsey H Elliott, Xiaoting Chen, Joseph Salomone, Praneet Chaturvedi, Preston A Schultz, Sai K Balchand, Jeffrey D Servetas, Aimée Zuniga, Rolf Zeller, Brian Gebelein, Matthew T Weirauch, Kevin A Peterson, Samantha A Brugmann

Faculty Research 2020

Despite a common understanding that Gli TFs are utilized to convey a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. Using the mouse model (Mus musculus), we demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the basic helix-loop-helix TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied …

Sexual Dimorphism In The Meiotic Requirement For Prdm9: A Mammalian Evolutionary Safeguard., Natalie Powers, Beth L Dumont, Chihiro Emori, Raman Akinyanju Lawal, Catherine Brunton, Kenneth Paigen, Mary Ann Handel, Ewelina Bolcun-Filas, Petko M. Petkov, Tanmoy Bhattacharyya

Faculty Research 2020

In many mammals, genomic sites for recombination are determined by the histone methyltransferase PRMD9. Some mouse strains lacking PRDM9 are infertile, but instances of fertility or semifertility in the absence of PRDM9 have been reported in mice, canines, and a human female. Such findings raise the question of how the loss of PRDM9 is circumvented to maintain fertility. We show that genetic background and sex-specific modifiers can obviate the requirement for PRDM9 in mice. Specifically, the meiotic DNA damage checkpoint protein CHK2 acts as a modifier allowing female-specific fertility in the absence of PRDM9. We also report that, in the …

Age And Genetic Background Modify Hybrid Male Sterility In House Mice., Samuel J Widmayer, Mary Ann Handel, David L Aylor

Faculty Research 2020

Hybrid male sterility (HMS) contributes to reproductive isolation commonly observed among house mouse (Mus musculus) subspecies, both in the wild and in laboratory crosses. Incompatibilities involving specific Prdm9 alleles and certain Chromosome (Chr) X genotypes are known determinants of fertility and HMS, and previous work in the field has demonstrated that genetic background modifies these two major loci. We constructed hybrids that have identical genotypes at Prdm9 and identical X chromosomes, but differ widely across the rest of the genome. In each case, we crossed female PWK/PhJ mice representative of the M. m. musculus subspecies to males from …

Endothelin 1-Induced Retinal Ganglion Cell Death Is Largely Mediated By Jun Activation., Olivia J Marola, Stephanie B Syc-Mazurek, Gareth R Howell, Richard T Libby

Faculty Research 2020

Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important …

Protocol For Isolation Of Cardiac Interstitial Cells From Adult Murine Hearts For Unbiased Single Cell Profiling., Elvira Forte, Sandra Daigle, Nadia Rosenthal

Faculty Research 2020

Interstitial cells have a crucial role in cardiac fibrosis and repair of the mammalian heart. Single-cell profiling using droplet-based technology has revolutionized the investigation of cell states and identities. Here, we present a protocol for the efficient isolation of high-quality live nucleated non-cardiomyocytes from adult murine heart, for unbiased single-cell RNA sequencing using 10× Chromium technology. This protocol has been applied to homeostatic and injured hearts from different mouse strains. For complete details on the use and execution of this protocol, please refer to Forte et al. (2020).

Nemf Mutations That Impair Ribosome-Associated Quality Control Are Associated With Neuromuscular Disease., Paige B Martin, Yu Kigoshi-Tansho, Roger B Sher, Gianina Ravenscroft, Jennifer E Stauffer, Rajesh Kumar, Ryo Yonashiro, Tina Müller, Christopher Griffith, William Allen, Davut Pehlivan, Tamar Haral, Martin Zenker, Denise Howting, Denny Schanze, Eissa A Faqeih, Naif A M Almontashiri, Reza Maroofian, Henry Houlden, Neda Mazaheri, Hamid Galehdari, Ganka Douglas, Jennifer E Posey, Monique Ryan, James R Lupski, Nigel G Laing, Claudio A P Joazeiro, Gregory A. Cox

Faculty Research 2020

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with …

Genetic Variation Regulates Opioid-Induced Respiratory Depression In Mice., Jason A. Bubier, Hao He, Vivek M. Philip, Tyler A. Roy, Christian Monroy Hernandez, Rebecca Bernat, Kevin D Donohue, Bruce F O'Hara, Elissa J Chesler

Faculty Research 2020

In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014. The diversion and misuse of prescription opioids along with increased use of drugs like heroin and fentanyl, has led to an epidemic in addiction and overdose deaths. The most common cause of opioid overdose and death is opioid-induced respiratory depression (OIRD), a life-threatening depression in respiratory rate thought to be caused by stimulation of opioid receptors in the inspiratory-generating regions of the brain. Studies in mice have revealed that variation in opiate lethality is associated with strain differences, suggesting that sensitivity to OIRD is genetically …

Identifying Mechanisms Of Normal Cognitive Aging Using A Novel Mouse Genetic Reference Panel., Amy R Dunn, Niran Hadad, Sarah M Neuner, Ji-Gang Zhang, Vivek M. Philip, Logan Dumitrescu, Timothy J Hohman, Jeremy H Herskowitz, Kristen M S O'Connell, Catherine Kaczorowski

Faculty Research 2020

Developing strategies to maintain cognitive health is critical to quality of life during aging. The basis of healthy cognitive aging is poorly understood; thus, it is difficult to predict who will have normal cognition later in life. Individuals may have higher baseline functioning (cognitive reserve) and others may maintain or even improve with age (cognitive resilience). Understanding the mechanisms underlying cognitive reserve and resilience may hold the key to new therapeutic strategies for maintaining cognitive health. However, reserve and resilience have been inconsistently defined in human studies. Additionally, our understanding of the molecular and cellular bases of these phenomena is …

A Novel Mouse Model Expressing Human Forms For Complement Receptors Cr1 And Cr2., Harriet M. Jackson, Kate E Foley, Rita O'Rourke, Timothy M Stearns, Dina Fathalla, B Paul Morgan, Gareth R Howell

Faculty Research 2020

BACKGROUND: The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer's disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known.

RESULTS: To decipher the roles of human CR1 and CR2 in health and disease, …

Naive Pluripotent Stem Cells Exhibit Phenotypic Variability That Is Driven By Genetic Variation., Daniel Ortmann, Stephanie Brown, Anne M Czechanski, Selcan Aydin, Daniele Muraro, Yuanhua Huang, Rute A Tomaz, Anna Osnato, Giovanni Canu, Brandon T Wesley, Daniel A Skelly, Oliver Stegle, Ted Choi, Gary A Churchill, Christopher L. Baker, Peter J Rugg-Gunn, Steven C. Munger, Laura G Reinholdt, Ludovic Vallier

Faculty Research 2020

Variability among pluripotent stem cell (PSC) lines is a prevailing issue that hampers not only experimental reproducibility but also large-scale applications and personalized cell-based therapy. This variability could result from epigenetic and genetic factors that influence stem cell behavior. Naive culture conditions minimize epigenetic fluctuation, potentially overcoming differences in PSC line differentiation potential. Here we derived PSCs from distinct mouse strains under naive conditions and show that lines from distinct genetic backgrounds have divergent differentiation capacity, confirming a major role for genetics in PSC phenotypic variability. This is explained in part through inconsistent activity of extra-cellular signaling, including the Wnt …

Identifying The Molecular Systems That Influence Cognitive Resilience To Alzheimer's Disease In Genetically Diverse Mice., Sarah E Heuer, Sarah M Neuner, Niran Hadad, Kristen M S O'Connell, Robert W Williams, Vivek M. Philip, Chris Gaiteri, Catherine Kaczorowski

Faculty Research 2020

Individual differences in cognitive decline during normal aging and Alzheimer's disease (AD) are common, but the molecular mechanisms underlying these distinct outcomes are not fully understood. We utilized a combination of genetic, molecular, and behavioral data from a mouse population designed to model human variation in cognitive outcomes to search for the molecular mechanisms behind this population-wide variation. Specifically, we used a systems genetics approach to relate gene expression to cognitive outcomes during AD and normal aging. Statistical causal-inference Bayesian modeling was used to model systematic genetic perturbations matched with cognitive data that identified astrocyte and microglia molecular networks as …

Cross-Species Analyses Identify Dlgap2 As A Regulator Of Age-Related Cognitive Decline And Alzheimer's Dementia., Andrew R Ouellette, Sarah M Neuner, Logan Dumitrescu, Laura C. Anderson, Daniel M. Gatti, Emily R Mahoney, Jason A. Bubier, Gary Churchill, Luanne L. Peters, Matthew J Huentelman, Jeremy H Herskowitz, Hyun-Sik Yang, Alexandra N Smith, Christiane Reitz, Brian W Kunkle, Charles C White, Philip L De Jager, Julie A Schneider, David A Bennett, Nicholas T Seyfried, Alzheimer's Disease Genetics Consortium, Elissa J Chesler, Niran Hadad, Timothy J Hohman, Catherine Kaczorowski

Faculty Research 2020

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical …

Dual Roles Of Neutrophils In Metastatic Colonization Are Governed By The Host Nk Cell Status., Peishan Li, Mingyang Lu, Jiayuan Shi, Li Hua, Zheng Gong, Qing Li, Leonard D. Shultz, Guangwen Ren

Faculty Research 2020

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell …

Term Matrix: A Novel Gene Ontology Annotation Quality Control System Based On Ontology Term Co-Annotation Patterns., Valerie Wood, Seth Carbon, Midori A Harris, Antonia Lock, Stacia R Engel, David P. Hill, Kimberly Van Auken, Helen Attrill, Marc Feuermann, Pascale Gaudet, Ruth C Lovering, Sylvain Poux, Kim M Rutherford, Christopher J Mungall

Faculty Research 2020

Biological processes are accomplished by the coordinated action of gene products. Gene products often participate in multiple processes, and can therefore be annotated to multiple Gene Ontology (GO) terms. Nevertheless, processes that are functionally, temporally and/or spatially distant may have few gene products in common, and co-annotation to unrelated processes probably reflects errors in literature curation, ontology structure or automated annotation pipelines. We have developed an annotation quality control workflow that uses rules based on mutually exclusive processes to detect annotation errors, based on and validated by case studies including the three we present here: fission yeast protein-coding gene annotations …