Digital Commons Network^™

The Long And Winding Road Towards New Treatments Against Lymphatic Filariasis And Onchocerciasis, Frederic Risch, Alexander Kazakov, Sabine Specht, Kenneth Pfarr, Peter U Fischer, Achim Hoerauf, Marc P Hübner

2020-Current year OA Pubs

Although lymphatic filariasis and onchocerciasis have been targeted for global elimination, these helminth infections are still a major public health problem across the tropics and subtropics. Despite decades of research, treatment options remain limited and drugs that completely clear the infections, and can be used on a large scale, are still unavailable. In the present review we discuss the strengths and weaknesses of currently available treatments and new ones in development. Novel candidates (corallopyronin A, DNDi-6166, emodepside, and oxfendazole) are currently moving through (pre)clinical development, while the development of two candidates (AWZ1066S and ABBV-4083/flubentylosin) was recently halted. The preclinical R&D …

Reduced Guanidinoacetate In Plasma Of Patients With Autosomal Dominant Fanconi Syndrome Due To Heterozygous P341l Gatm Variant And Study Of Organoids Towards Treatment, Ignacio Portales-Castillo, Rhea Singal, Jong Hee Song, Minsoo Son, Young Ah Goo, Ariella Coler-Reilly, Benjamin D Humphreys, Roberto Civitelli, Et Al.

2020-Current year OA Pubs

Autosomal dominant Fanconi syndrome due to a

Mutant Nrf2e79q Enhances The Promotion And Progression Of A Subset Of Oncogenic Ras Keratinocytes And Skin Tumors, John G Witherspoon, Jonathan R Hall, Dereje Jima, Hannah M Atkins, Nathan T Wamsley, Michael B Major, Bernard E Weissman, Robert C Smart

2020-Current year OA Pubs

Squamous cell carcinomas (SCCs), including lung, head & neck, bladder, and skin SCCs often display constitutive activation of the KEAP1-NRF2 pathway. Constitutive activation is achieved through multiple mechanisms, including activating mutations in NFE2L2 (NRF2). To determine the functional consequences of Nrf2 activation on skin SCC development, we assessed the effects of mutant Nrf2

An Interpretable Machine Learning-Based Cerebrospinal Fluid Proteomics Clock For Predicting Age Reveals Novel Insights Into Brain Aging, Justin Melendez, Yun Ju Sung, Miranda Orr, Andrew Yoo, Suzanne Schindler, Carlos Cruchaga, Randall Bateman

2020-Current year OA Pubs

Machine learning can be used to create "biologic clocks" that predict age. However, organs, tissues, and biofluids may age at different rates from the organism as a whole. We sought to understand how cerebrospinal fluid (CSF) changes with age to inform the development of brain aging-related disease mechanisms and identify potential anti-aging therapeutic targets. Several epigenetic clocks exist based on plasma and neuronal tissues; however, plasma may not reflect brain aging specifically and tissue-based clocks require samples that are difficult to obtain from living participants. To address these problems, we developed a machine learning clock that uses CSF proteomics to …

A Damaging Col6a3 Variant Alters The Mir31hg-Regulated Response Of Chondrocytes In Neocartilage Organoids To Hyperphysiologic Mechanical Loading, Niek Gc Bloks, Zainab Harissa, Giorgia Mazzini, Shaunak S Adkar, Amanda R Dicks, Ghazaleh Hajmousa, Nancy Steward, Roman I Koning, Aat Mulder, Berend B R De Koning, Margreet Kloppenburg, Rodrigo Coutinho De Almeida, Yolande Fm Ramos, Farshid Guilak, Ingrid Meulenbelt

2020-Current year OA Pubs

The pericellular matrix (PCM), with its hallmark proteins collagen type VI (COLVI) and fibronectin (FN), surrounds chondrocytes and is critical in transducing the biomechanical cues. To identify genetic variants that change protein function, exome sequencing is performed in a patient with symptomatic OA at multiple joint sites. A predicted damaging variant in COL6A3 is identified and introduced by CRISPR-Cas9 genome engineering in two established human induced pluripotent stem cell-derived in-vitro neocartilage organoid models. The downstream effects of the COL6A3 variant on the chondrocyte phenotypic state are studied by a multi-omics (mRNA and lncRNA) approach in interaction with hyper-physiological mechanical loading …

Structure Of A Truncated Human Glcnac-1-Phosphotransferase Variant Reveals The Basis For Its Hyperactivity, Hua Li, Balraj Doray, Benjamin C Jennings, Wang-Sik Lee, Lin Liu, Stuart Kornfeld, Huilin Li

2020-Current year OA Pubs

Mutations that cause loss of function of GlcNAc-1-phosphotransferase (PTase) lead to the lysosomal storage disorder mucolipidosis II. PTase is the key enzyme of the mannose 6-phosphate (M6P) targeting system that is responsible for tagging lysosomal hydrolases with the M6P moiety for their delivery to the lysosome. We had previously generated a truncated hyperactive form of PTase termed S1S3 which was shown to notably increase the phosphorylation level of secreted lysosomal enzymes and enhance their uptake by cells. Here, we report the 3.4 Å cryo-EM structure of soluble S1S3 lacking both transmembrane domains and cytosolic tails. The structure reveals a high …

The Physiologic Basis Of Molecular Therapeutics For Peripheral Nerve Injury: A Primer, Marie C Spezia, Christopher J Dy, David M Brogan

2020-Current year OA Pubs

Peripheral nerve injuries affect a significant number of patients who experience trauma affecting the hand and upper extremity. Improving unsatisfactory outcomes from repair of these injuries remains a clinical challenge despite advancements in microsurgical repair. Imperfections of the nerve regeneration process, including imprecise reinnervation, distal axon degradation, and muscular atrophy, complicate the repair process. However, the capacity for peripheral nerves to regenerate offers an avenue for therapeutic advancement. Regeneration is a temporally and spatially dynamic process coordinated by Schwann cells and neurons among other cell types. Neurotrophic factors are a primary means of controlling cell growth and differentiation in the …

Endogenous Base Damage As A Driver Of Genomic Instability In Homologous Recombination-Deficient Cancers, Lindsey N Aubuchon, Priyanka Verma

2020-Current year OA Pubs

Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway. Both familial and somatic loss of function mutation(s) in various HR genes predispose to a variety of cancer types, underscoring the importance of error-free repair of DSBs in human physiology. While environmental sources of DSBs have been known, more recent studies have begun to uncover the role of endogenous base damage in leading to these breaks. Base damage repair intermediates often consist of single-strand breaks, which if left unrepaired, can lead to DSBs as the replication fork encounters these lesions. This review summarizes various sources of endogenous base …

Trem2 On Microglia Cell Surface Binds To And Forms Functional Binary Complexes With Heparan Sulfate Modified With 6-O-Sulfation And Iduronic Acid, Ilayda Ozsan Mcmillan, Li Liang, Guowei Su, Xuehong Song, Kelly Drago, Hua Yang, Claudia Alvarez, Amika Sood, James Gibson, Robert J Woods, Chunyu Wang, Jian Liu, Fuming Zhang, Tom J Brett, Lianchun Wang

2020-Current year OA Pubs

The triggering receptor expressed on myeloid cells-2 (TREM2), a pivotal innate immune receptor, orchestrates functions such as inflammatory responses, phagocytosis, cell survival, and neuroprotection. TREM2 variants R47H and R62H have been associated with Alzheimer's disease, yet the underlying mechanisms remain elusive. Our previous research established that TREM2 binds to heparan sulfate (HS) and variants R47H and R62H exhibit reduced affinity for HS. Building upon this groundwork, our current study delves into the interplay between TREM2 and HS and its impact on microglial function. We confirm TREM2's binding to cell surface HS and demonstrate that TREM2 interacts with HS, forming HS-TREM2 …

Tauroursodeoxycholic Acid Ameliorates Renal Injury Induced By Col4a3 Mutation, Shuwen Yu, Teija Suhas, Meei-Hua Lin, Jeffrey H Miner, Et Al.

2020-Current year OA Pubs

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed …

Rhesus Rotavirus Nsp1 Mediates Extra-Intestinal Infection And Is A Contributing Factor For Biliary Obstruction, Enkai Li, Ningguo Feng, Qiru Zeng, Liliana Sanchez-Tacuba, Takahiro Kawagishi, Grace Branham, Gaopeng Hou, Zemin Wang, Harry B. Greenberg, Siyuan Ding

2020-Current year OA Pubs

We previously demonstrated that in Ifnar1-/-Ifngr1-/- or Stat1-/- suckling mice lacking intact type I and type II interferon (IFN) signaling, rhesus rotavirus (RRV) infection causes a lethal disease with clinical manifestations similar to biliary atresia, including acholic stools, oily fur, growth retardation, and excess mortality. Elevated levels of viral RNA are detected in the bile ducts and liver of diseased pups together with severe inflammatory responses in these tissues. However, the viral determinants and the molecular mechanisms driving this process remain incompletely understood. Using an optimized rotavirus (RV) reverse genetics system, we generated a panel of recombinant RVs that encode …

Tissue-Specific Features Of Innate Lymphoid Cells In Antiviral Defense, Sytse J Piersma

2020-Current year OA Pubs

Innate lymphocytes (ILCs) rapidly respond to and protect against invading pathogens and cancer. ILCs include natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells and include type I, type II, and type III immune cells. While NK cells have been well recognized for their role in antiviral immunity, other ILC subtypes are emerging as players in antiviral defense. Each ILC subset has specialized functions that uniquely impact the antiviral immunity and health of the host depending on the tissue microenvironment. This review focuses on the specialized functions of each ILC subtype and their roles in antiviral …

A Novel Antigen Biomarker For Detection Of High-Level Of Loa Loa Microfilaremia, Sarah E Greene, Yuefang Huang, Kerstin Fischer, Bruce A. Rosa, John Martin, Makedonka Mitreva, Devyn Yates, Samuel Wanji, Joseph Kamgno, Philip J. Budge, Gary J. Weil, Peter U. Fischer

2020-Current year OA Pubs

BACKGROUND: Loiasis is a disease caused by the nematode Loa loa. Serious adverse events sometimes occur in people with heavy L. loa microfilaremia after ivermectin treatment. In regions of Central Africa where loiasis is endemic, this significantly impedes global elimination programs for lymphatic filariasis and onchocerciasis that use mass distribution of ivermectin. Improved diagnostic tests to identify individuals at increased risk of serious adverse events could facilitate efforts to eliminate lymphatic filariasis and onchocerciasis in this region.

METHODS AND FINDINGS: We previously identified the L. loa protein Ll-Bhp-1 in loiasis patient sera. Here, we further characterize Ll-Bhp-1 and report development …

Repeat Modules And N-Linked Glycans Define Structure And Antigenicity Of A Critical Enterotoxigenic E. Coli Adhesin, Zachary T. Berndsen, Marjahan Akhtar, Mahima Thapa, Tim J. Vickers, Aaron Schmitz, Pardeep Kumar, Nazia Khatoon, Alaullah Sheikh, Melissa Hamrick, Jackson S. Turner, Ali H. Ellebedy, James M. Fleckenstein, Et Al.

2020-Current year OA Pubs

Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of cases of infectious diarrhea annually, predominantly in children from low-middle income regions. Notably, in children, as well as volunteers challenged with ETEC, diarrheal severity is significantly increased in blood group A (bgA) individuals. EtpA, is a secreted glycoprotein adhesin that functions as a blood group A lectin to promote critical interactions between ETEC and blood group A glycans on intestinal epithelia for effective bacterial adhesion and toxin delivery. EtpA is highly immunogenic resulting in robust antibody responses following natural infection and experimental challenge of volunteers with ETEC. To understand how EtpA …

Spatial Single-Cell Isotope Tracing Reveals Heterogeneity Of De Novo Fatty Acid Synthesis In Cancer, Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Mohammed Shahraz, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov

2020-Current year OA Pubs

While heterogeneity is a key feature of cancer, understanding metabolic heterogeneity at the single-cell level remains a challenge. Here we present

Loss Of Periostin Function Impairs Ligament Fibroblast Activity And Facilitates Ros-Mediated Cellular Senescence, Muhammad Farooq Rai, Xin Duan, Mingming Yan, Robert H Brophy, Lei Cai

2020-Current year OA Pubs

Anterior cruciate ligament (ACL) injuries pose a significant challenge due to their limited healing potential, often resulting in premature arthritis. The factors and mechanisms contributing to this inadequate healing process remain elusive. During the acute phase of injury, ACL tissues express elevated periostin levels that decline over time. The functional significance of periostin in ligament biology remains understudied. In this study, we investigated the functional and mechanistic implications of periostin deficiency in ACL biology, utilizing ligament fibroblasts derived from patients and a murine model of ACL rupture. Our investigations unveiled that periostin knockdown compromised fibroblast growth characteristics, hindered the egress …

Regulatory Transposable Elements In The Encyclopedia Of Dna Elements, Alan Y Du, Jason D Chobirko, Xiaoyu Zhuo, Cédric Feschotte, Ting Wang

2020-Current year OA Pubs

Transposable elements (TEs) comprise ~50% of our genome, but knowledge of how TEs affect genome evolution remains incomplete. Leveraging ENCODE4 data, we provide the most comprehensive study to date of TE contributions to the regulatory genome. We find 236,181 (~25%) human candidate cis-regulatory elements (cCREs) are TE-derived, with over 90% lineage-specific since the human-mouse split, accounting for 8-36% of lineage-specific cCREs. Except for SINEs, cCRE-associated transcription factor (TF) motifs in TEs are derived from ancestral TE sequence more than expected by chance. We show that TEs may adopt similar regulatory activities of elements near their integration site. Since human-mouse divergence, …

Histone H3.3 Lysine 9 And 27 Control Repressive Chromatin At Cryptic Enhancers And Bivalent Promoters, Matteo Trovato, Daria Bunina, Umut Yildiz, Nadine Fernandez-Novel Marx, Michael Uckelmann, Vita Levina, Yekaterina Perez, Ana Janeva, Benjamin A Garcia, Chen Davidovich, Judith B Zaugg, Kyung-Min Noh

2020-Current year OA Pubs

Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutate histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleash cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to …

West Nile Virus Triggers Intestinal Dysmotility Via T Cell-Mediated Enteric Nervous System Injury, Hana Janova, Fang R. Zhao, Pritesh Desai, Matthias Mack, Larissa B. Thackray, Thaddeus S. Stappenbeck, Michael S. Diamond

2020-Current year OA Pubs

Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus West Nile virus (WNV) and demonstrated intestinal transit defects. Here, we found that within 1 week of WNV infection, enteric neurons and glia became damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4+ and CD8+ T cells damaged the enteric nervous system (ENS) and glia, which led to …

Structural Basis For Mouse Lag3 Interactions With The Mhc Class Ii Molecule I-Ab, Qianqian Ming, Daniel Antfolk, David A Price, Anna Manturova, Elliot Medina, Srishti Singh, Charlotte Mason, Timothy H Tran, Keiran S M Smalley, Daisy W Leung, Vincent C Luca

2020-Current year OA Pubs

The immune checkpoint protein, Lymphocyte activation gene-3 (LAG3), binds Major Histocompatibility Complex Class II (MHC-II) and suppresses T cell activation. Despite the recent FDA approval of a LAG3 inhibitor for the treatment of melanoma, how LAG3 engages MHC-II on the cell surface remains poorly understood. Here, we determine the 3.84 Å-resolution structure of mouse LAG3 bound to the MHC-II molecule I-A

Cognitive Effects Of Simulated Galactic Cosmic Radiation Are Mediated By Apoe Status, Sex, And Environment In App Knock-In Mice, Laura Wieg, Jason C Ciola, Caroline C Wasén, Fidelia Gaba, Brianna R Colletti, Maren K Schroeder, Robert G Hinshaw, Millicent N Ekwudo, David M Holtzman, Takashi Saito, Hiroki Sasaguri, Takaomi C Saido, Laura M Cox, Cynthia A Lemere

2020-Current year OA Pubs

Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer's disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.75 Gy five-ion GCRsim or 2 Gy gamma radiation (IRR) in 14-month-old female and male APP

Diet-Induced Obesity Induces Transcriptomic Changes In Neuroimmunometabolic-Related Genes In The Striatum And Olfactory Bulb, Rosario B Jaime-Lara, Claudia Colina-Prisco, Marcel De Jesus Vega, Sarah Williams, Ted Usdin, Bridget Matikainen-Ankney, Alayna Kinkead, Brianna Brooks, Yupeng Wang, Alexis T Franks, Alexxai Kravitz, Paule V Joseph

2020-Current year OA Pubs

The incidence of obesity has markedly increased globally over the last several decades and is believed to be associated with the easier availability of energy-dense foods, including high-fat foods. The reinforcing hedonic properties of high-fat foods, including olfactory cues, activate reward centers in the brain, motivating eating behavior. Thus, there is a growing interest in the understanding of the genetic changes that occur in the brain that are associated with obesity and eating behavior. This growing interest has paralleled advances in genomic methods that enable transcriptomic-wide analyses. Here, we examined the transcriptomic-level differences in the olfactory bulb and striatum, regions …

Signaling Modulation Mediated By Ligand Water Interactions With The Sodium Site At Μor, Rohini S Ople, Nokomis Ramos-Gonzalez, Sarah M Bernhard, Kevin Appourchaux, Sashrik Sribhashyam, Balazs R Varga, Susruta Majumdar, Et Al.

2020-Current year OA Pubs

The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported a novel strategy to design functionally selective opioids by targeting the sodium binding allosteric site in μOR with a supraspinally active analgesic named

Dual Color Optogenetic Tool Enables Heart Arrest, Bradycardic, And Tachycardic Pacing In Drosophila Melanogaster, Elena Gracheva, Yuxuan Wang, Jiantao Zhu, Fei Wang, Abigail Matt, Matthew Fishman, Hongwu Liang, Chao Zhou

2020-Current year OA Pubs

In order to facilitate cardiovascular research to develop non-invasive optical heart pacing methods, we have generated a double-transgenic Drosophila melanogaster (fruit fly) model suitable for optogenetic pacing. We created a fly stock with both excitatory H134R-ChR2 and inhibitory eNpHR2.0 opsin transgenes. Opsins were expressed in the fly heart using the Hand-GAL4 driver. Here we describe Hand > H134R-ChR2; eNpHR2.0 model characterization including bi-directional heart control (activation and inhibition) upon illumination of light with distinct wavelengths. Optical control and real-time visualization of the heart function were achieved non-invasively using an integrated light stimulation and optical coherence microscopy (OCM) system. OCM produced high-speed …

Baf155 Controls Hematopoietic Differentiation And Regeneration Through Chromatin Priming, Jun Wu, Changxu Fan, Ashraf Ul Kabir, Karen Krchma, Minseo Kim, Yoojung Kwon, Xiaoyun Xing, Ting Wang, Kyunghee Choi

2020-Current year OA Pubs

Chromatin priming promotes cell-type-specific gene expression, lineage differentiation, and development. The mechanism of chromatin priming has not been fully understood. Here, we report that mouse hematopoietic stem and progenitor cells (HSPCs) lacking the Baf155 subunit of the BAF (BRG1/BRM-associated factor) chromatin remodeling complex produce a significantly reduced number of mature blood cells, leading to a failure of hematopoietic regeneration upon transplantation and 5-fluorouracil (5-FU) injury. Baf155-deficient HSPCs generate particularly fewer neutrophils, B cells, and CD8

Kmt2c Restricts G-Csf-Driven Hsc Mobilization And Granulocyte Production In A Methyltransferase-Independent Manner, Helen C Wang, Ran Chen, Wei Yang, Yanan Li, Rohini Muthukumar, Riddhi M Patel, Emily B Casey, Elisabeth Denby, Jeffrey A Magee

2020-Current year OA Pubs

Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced …

Nonreciprocity In Chikv And Mayv Vaccine-Elicited Protection, Whitney C Weber, Takeshi F Andoh, Craig N Kreklywich, Zachary J Streblow, Michael Denton, Magdalene M Streblow, John M Powers, Gauthami Sulgey, Samuel Medica, Igor Dmitriev, David T Curiel, Nicole N Haese, Daniel N Streblow

2020-Current year OA Pubs

Chikungunya virus (CHIKV) is a pathogenic arthritogenic alphavirus responsible for large-scale human epidemics for which a vaccine was recently approved for use. Mayaro virus (MAYV) is a related emerging alphavirus with epidemic potential with circulation overlap potential with CHIKV. We previously reported the ability of a non-replicating human adenovirus (AdV)-vectored vaccine expressing the MAYV structural polyprotein to protect against disease in mice following challenge with MAYV, CHIKV and UNAV. Herein, we evaluated mouse immunity and protective efficacy for an AdV-CHIKV full structural polyprotein vaccine in combination with heterologous AdV-MAYV prime/boost regimens versus vaccine coadministration. Heterologous prime/boost regimens skewed immunity toward …

Clinical Features And Disease Progression In Older Individuals With Rett Syndrome, Jeffrey L Neul, Timothy A Benke, Eric D Marsh, Bernhard Suter, Cary Fu, Robin C Ryther, Steven A Skinner, David N Lieberman, Timothy Feyma, Arthur Beisang, Peter Heydemann, Sarika U Peters, Amitha Ananth, Alan K Percy

2020-Current year OA Pubs

Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in

Mice Lacking Astn2 Have Asd-Like Behaviors And Altered Cerebellar Circuit Properties, Michalina Hanzel, Kayla Fernando, Susan E Maloney, Zachi Horn, Shiaoching Gong, Kärt Mätlik, Jiajia Zhao, H Amalia Pasolli, Søren Heissel, Joseph D Dougherty, Court Hull, Mary E Hatten

2020-Current year OA Pubs

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with

Single-Cell Analysis Of Innate Spinal Cord Regeneration Identifies Intersecting Modes Of Neuronal Repair, Vishnu Muraleedharan Saraswathy, Lili Zhou, Mayssa H Mokalled

2020-Current year OA Pubs

Adult zebrafish have an innate ability to recover from severe spinal cord injury. Here, we report a comprehensive single nuclear RNA sequencing atlas that spans 6 weeks of regeneration. We identify cooperative roles for adult neurogenesis and neuronal plasticity during spinal cord repair. Neurogenesis of glutamatergic and GABAergic neurons restores the excitatory/inhibitory balance after injury. In addition, a transient population of injury-responsive neurons (iNeurons) show elevated plasticity 1 week post-injury. We found iNeurons are injury-surviving neurons that acquire a neuroblast-like gene expression signature after injury. CRISPR/Cas9 mutagenesis showed iNeurons are required for functional recovery and employ vesicular trafficking as an …