Publications

Hope Center member publications

List of publications for the week of December 6, 2021

A MYT1L syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation” (2021) Neuron

A MYT1L syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation
(2021) Neuron, 109 (23), pp. 3775-3792.e14. 

Chen, J.a b , Lambo, M.E.c , Ge, X.d , Dearborn, J.T.e , Liu, Y.a b , McCullough, K.B.a b , Swift, R.G.a b , Tabachnick, D.R.a b , Tian, L.c , Noguchi, K.b f , Garbow, J.R.d f g , Constantino, J.N.b f , Gabel, H.W.h , Hengen, K.B.c , Maloney, S.E.b f , Dougherty, J.D.a b f

a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
f Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, United States
g Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
h Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Human genetics have defined a new neurodevelopmental syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes intellectual disability, autism, ADHD, obesity, and brain anomalies is unknown. Here, we developed a Myt1l haploinsufficient mouse model that develops obesity, white-matter thinning, and microcephaly, mimicking common clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1l gene-target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. Myt1l haploinsufficiency also results in behavioral anomalies, including hyperactivity, muscle weakness, and social alterations, with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies. © 2021 Elsevier Inc.

Author Keywords
ADHD;  ASD;  Autism;  Chromatin Accessibility;  Hyperactivity;  ID;  Neuronal Differentiation;  Social Motivation;  Transcription

Funding details
National Institutes of HealthNIH5UL1TR002345, R01MH107515, R01MH124808
Brain and Behavior Research FoundationBBRF
Washington University in St. LouisWUSTL
Institute of Clinical and Translational SciencesICTSP50 HD103525
Washington University School of Medicine in St. LouisWUSM
Penn State Clinical and Translational Science InstituteCTSI

Document Type: Article
Publication Stage: Final
Source: Scopus

Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis” (2021) Nature Communications

Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis
(2021) Nature Communications, 12 (1), art. no. 6809, . 

Weston, K.P.a , Gao, X.a , Zhao, J.a , Kim, K.-S.a , Maloney, S.E.b , Gotoff, J.c , Parikh, S.d , Leu, Y.-C.e , Wu, K.-P.e , Shinawi, M.f , Steimel, J.P.g , Harrison, J.S.h , Yi, J.J.a

a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Pediatrics, Geisinger Medical Center, Danville, PA 17822, United States
d Department of Neurogenetics, Neurosciences Institute, Cleveland Clinic, Cleveland, OH 44106, United States
e Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
f Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO 63110, United States
g Deparment of Mechanical Engineering, University of the Pacific, Stockton, CA 95211, United States
h Department of Chemistry, University of the Pacific, Stockton, CA 95211, United States

Abstract
The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders. © 2021, The Author(s).

Funding details
National Institute of Mental HealthNIMHR01MH122786
Brain and Behavior Research FoundationBBRF
Alfred P. Sloan Foundation
Simons FoundationSF387972
Whitehall Foundation
Angelman Syndrome FoundationASF
National Alliance for Research on Schizophrenia and DepressionNARSAD

Document Type: Article
Publication Stage: Final
Source: Scopus

A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function” (2021) Science Advances

A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function
(2021) Science Advances, 7 (48), art. no. eabf6935, . 

Xiao, M.-F.a , Roh, S.-E.a , Zhou, J.a , Chien, C.-C.a , Lucey, B.P.b , Craig, M.T.c , Hayes, L.N.a , Coughlin, J.M.d , Markus Leweke, F.e f , Jia, M.a , Xu, D.a , Zhou, W.g , Conover Talbot, C.h , Arnold, D.B.i , Staley, M.d , Jiang, C.d , Reti, I.M.d , Sawa, A.a d j k , Pelkey, K.A.l , McBain, C.J.l , Savonenko, A.m , Worley, P.F.a n

a Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom
d Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
e Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
f Youth Mental Health Team, Brain and Mind Centre, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
g Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
h Transcriptomics and Deep Sequencing Core Facility, Johns Hopkins University School of Medicine, Baltimore, MD, United States
i Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, United States
j Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
k Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States
l Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, Bethesda, MD, United States
m Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
n Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress. © 2021 American Association for the Advancement of Science. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Brief Electrical Stimulation Accelerates Axon Regeneration and Promotes Recovery Following Nerve Transection and Repair in Mice” (2021) The Journal of Bone and Joint Surgery. American Volume

Brief Electrical Stimulation Accelerates Axon Regeneration and Promotes Recovery Following Nerve Transection and Repair in Mice
(2021) The Journal of Bone and Joint Surgery. American Volume, 103 (20), p. e80. 

Sayanagi, J., Acevedo-Cintrón, J.A., Pan, D., Schellhardt, L., Hunter, D.A., Snyder-Warwick, A.K., Mackinnon, S.E., Wood, M.D.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Clinical outcomes following nerve injury repair can be inadequate. Pulsed-current electrical stimulation (ES) is a therapeutic method that facilitates functional recovery by accelerating axon regeneration. However, current clinical ES protocols involve the application of ES for 60 minutes during surgery, which can increase operative complexity and time. Shorter ES protocols could be a strategy to facilitate broader clinical adoption. The purpose of the present study was to determine if a 10-minute ES protocol could improve outcomes. METHODS: C57BL/6J mice were randomized to 3 groups: no ES, 10 minutes of ES, and 60 minutes of ES. In all groups, the sciatic nerve was transected and repaired, and, in the latter 2 groups, ES was applied after repair. Postoperatively, changes to gene expression from dorsal root ganglia were measured after 24 hours. The number of motoneurons regenerating axons was determined by retrograde labeling at 7 days. Histomorphological analyses of the nerve were performed at 14 days. Function was evaluated serially with use of behavioral tests up to 56 days postoperatively, and relative muscle weight was evaluated. RESULTS: Compared with the no-ES group, both ES groups demonstrated increased regeneration-associated gene expression within dorsal root ganglia. The 10-minute and 60-minute ES groups demonstrated accelerated axon regeneration compared with the no-ES group based on increased numbers of labeled motoneurons regenerating axons (mean difference, 202.0 [95% confidence interval (CI), 17.5 to 386.5] and 219.4 [95% CI, 34.9 to 403.9], respectively) and myelinated axon counts (mean difference, 559.3 [95% CI, 241.1 to 877.5] and 339.4 [95% CI, 21.2 to 657.6], respectively). The 10-minute and 60-minute ES groups had improved behavioral recovery, including on grid-walking analysis, compared with the no-ES group (mean difference, 11.9% [95% CI, 3.8% to 20.0%] and 10.9% [95% CI, 2.9% to 19.0%], respectively). There was no difference between the ES groups in measured outcomes. CONCLUSIONS: A 10-minute ES protocol accelerated axon regeneration and facilitated functional recovery. CLINICAL RELEVANCE: The brief (10-minute) ES protocol provided similar benefits to the 60-minute protocol in an acute sciatic nerve transection/repair mice model and merits further studies. Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.

Document Type: Article
Publication Stage: Final
Source: Scopus

Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss” (2021) Cell Reports

Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss
(2021) Cell Reports, 37 (3), art. no. 109872, . 

Wu, T.a d , Zhu, J.a c , Strickland, A.a , Ko, K.W.b , Sasaki, Y.a , Dingwall, C.B.a , Yamada, Y.a , Figley, M.D.b , Mao, X.a , Neiner, A.a , Bloom, A.J.a c , DiAntonio, A.b c , Milbrandt, J.a c

a Department of Genetics, Washington University Medical School, St. Louis, MO 63110, United States
b Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110, United States
c Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine in Saint Louis, St. Louis, MO 63114, United States
d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might activate SARM1. Here, we show the nicotinamide analog 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN, which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration, and neuronal death. In mice, systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to the peripheral nerve induces SARM1-dependent axon degeneration. We identify 2-aminopyridine as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity and suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy. © 2021 The Author(s)

Author Keywords
base exchange reaction;  mass spectrometry;  metabolism;  myelin;  NAMPT;  neurolytic block;  NMNAT;  sciatic nerve;  tibial nerve;  Vacor

Funding details
National Institutes of HealthNIHR01CA219866, R01NS087632, RF1AG013730

Document Type: Article
Publication Stage: Final
Source: Scopus

Scalable and modular wireless-network infrastructure for large-scale behavioural neuroscience” (2021) Nature Biomedical Engineering

Scalable and modular wireless-network infrastructure for large-scale behavioural neuroscience
(2021) Nature Biomedical Engineering, . 

Qazi, R.a b , Parker, K.E.c d e f , Kim, C.Y.a , Rill, R.g , Norris, M.R.c d e f h , Chung, J.g , Bilbily, J.c d e f i , Kim, J.R.c d e f , Walicki, M.C.c d e f , Gereau, G.B.c d e f , Lim, H.g , Xiong, Y.j , Lee, J.R.k , Tapia, M.A.l , Kravitz, A.V.i , Will, M.J.l , Ha, S.g , McCall, J.G.c d e f h , Jeong, J.-W.a

a School of Electrical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
b Department of Electrical, Computer and Energy Engineering, University of Colorado, Boulder, CO, United States
c Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy in St. Louis, St. Louis, MO, United States
e Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St. Louis and Washington University School of Medicine, St. Louis, MO, United States
f Washington University Pain Center, Washington University in St. Louis, St. Louis, MO, United States
g Department of Computer Science, University of Colorado Boulder, Boulder, CO, United States
h Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
i Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
j Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, United States
k Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO, United States
l Department of Psychological Sciences, University of Missouri, Columbia, MO, United States

Abstract
The use of rodents to acquire understanding of the function of neural circuits and of the physiological, genetic and developmental underpinnings of behaviour has been constrained by limitations in the scalability, automation and high-throughput operation of implanted wireless neural devices. Here we report scalable and modular hardware and software infrastructure for setting up and operating remotely programmable miniaturized wireless networks leveraging Bluetooth Low Energy for the study of the long-term behaviour of large groups of rodents. The integrated system allows for automated, scheduled and real-time experimentation via the simultaneous and independent use of multiple neural devices and equipment within and across laboratories. By measuring the locomotion, feeding, arousal and social behaviours of groups of mice or rats, we show that the system allows for bidirectional data transfer from readily available hardware, and that it can be used with programmable pharmacological or optogenetic stimulation. Scalable and modular wireless-network infrastructure should facilitate the remote operation of fully automated large-scale and long-term closed-loop experiments for the study of neural circuits and animal behaviour. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
National Institutes of HealthNIHR01NS117899, R25 MH112473
Oak Ridge Associated UniversitiesORAU
Ministry of Science, ICT and Future PlanningMSIPNRF-2020M3A9G8018572, NRF-2021R1A2C4001483
National Research Foundation of KoreaNRF

Document Type: Article
Publication Stage: Article in Press
Source: Scopus