DOCSLIB.ORG

Differentiation and Localization of Interneurons In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Differentiation and Localization of Interneurons In Gray de Cristoforis et al. Molecular Brain (2020) 13:85 https://doi.org/10.1186/s13041-020-00623-3 RESEARCH Open Access Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression Angelica Gray de Cristoforis1,2,3, Francesco Ferrari3,4, Frédéric Clotman5 and Tanja Vogel1,2,6* Abstract Genetic and epigenetic factors contribute to the development of the spinal cord. Failure in correct exertion of the developmental programs, including neurulation, neural tube closure and neurogenesis of the diverse spinal cord neuronal subtypes results in defects of variable severity. We here report on the histone methyltransferase Disruptor of Telomeric 1 Like (DOT1L), which mediates histone H3 lysine 79 (H3K79) methylation. Conditional inactivation of DOT1L using Wnt1-cre as driver (Dot1l-cKO) showed that DOT1L expression is essential for spinal cord neurogenesis and localization of diverse neuronal subtypes, similar to its function in the development of the cerebral cortex and cerebellum. Transcriptome analysis revealed that DOT1L deficiency favored differentiation over progenitor proliferation. Dot1l-cKO mainly decreased the numbers of dI1 interneurons expressing Lhx2. In contrast, Lhx9 expressing dI1 interneurons did not change in numbers but localized differently upon Dot1l-cKO. Similarly, loss of DOT1L affected localization but not generation of dI2, dI3, dI5, V0 and V1 interneurons. The resulting derailed interneuron patterns might be responsible for increased cell death, occurrence of which was restricted to the late developmental stage E18.5. Together our data indicate that DOT1L is essential for subtype-specific neurogenesis, migration and localization of dorsal and ventral interneurons in the developing spinal cord, in part by regulating transcriptional activation of Lhx2. Keywords: Spinal cord, Interneuron, Specification, Localization, Methyltransferase, DOT1L, Epigenetics Introduction types. Many factors take part in the precise processes that The central nervous system (CNS), composed of spinal initiate and maintain cell-specific transcriptional profiles, cord and brain, forms through invagination of the neural which are necessary for both neurulation and the subse- ectoderm and fusion of the neural folds to generate the quent specification of the diverse neuronal subpopulations neural tube, in a process called neurulation. Fusion of the during neural tube development. neural folds and closure of the neural tube is completed Opposite gradients of signaling pathways, for example between E8.75 and E10 in the mouse [1]. A delicate mo- those of Bone Morphogenetic Protein (BMP) and lecular network tightly orchestrates the development of Wingless-related integration site (WNT) from the roof- the spinal cord in its entire complexity of different cell plate, or Sonic Hedgehog (SHH) from the floorplate, tightly regulate the establishment of diverse progenitor * Correspondence: [email protected] classes along the dorsoventral axis [2]. According to differ- 1Department of Molecular Embryology, Institute of Anatomy and Cell ent marker gene expression patterns and response to Biology, Faculty of Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany signaling molecules, the developing spinal cord is subdi- 2Spemann Graduate School of Biology and Medicine (SGBM), vided into six dorsal progenitor classes (dp1–6 inter- Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany neuron progenitors) and five ventral progenitor classes Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gray de Cristoforis et al. Molecular Brain (2020) 13:85 Page 2 of 20 (p0–3 interneuron progenitors and pMN motor neurons cord development are still unresolved. Histone H3 lysine progenitors). Two waves of neurogenesis lead to the methylation occurs at different positions including K4, differentiation of the progenitor classes into mature inter- K9 or K27. Recently, modifications of K79 were linked neurons or motor neurons (MN) [3]. In the first wave, with NTD. Specifically, attenuation of H3K79 dimethyla- which takes place between E9.0-E12.5, dorsal interneuron tion (H3K79me2) correlated with NTD occurrence in classes (dI1–6) [4–9] and ventral interneurons (V0–3) brain samples of human embryos presenting with spina differentiate along with MN [10–15], each from the re- bifida [43]. Further, high levels of H3K79 homocysteiny- spective progenitor class. A smaller subset of dorsal inter- lation (Hcy), in place of methylation at this position, neurons, dILA and dILB, is generated in the second wave correlated with decreased expression of specific genes, between E11.5 and E13.5 [6, 9, 16, 17]. Maturing interneu- e.g. Smarca4, Cecr2 and Dnmt3b, which are known to rons migrate from the ventricular zone into the mantle cause NTD upon disbalanced transcription [44]. H3K79 zone to their final position to build and to integrate into mono-, di- and trimethylation (H3K79 me1, me2 or functional neuronal circuits. The dorsal populations dI1- me3) is mainly conferred by the Disruptor of Telomeric dI4 and dILA integrate into circuits involved in proprio- Silencing 1 Like (DOT1L) in mammals [45]. DOT1L ception or touch-related motor control [4, 18, 19], dI4/ function has been linked to a range of cellular processes dILA and dI5/dILB populations into networks transmitting including transcriptional activation, resume of transcrip- information for pain, thermal sensation, itch and touch tion after DNA damage, or cell cycle progression [45]. [20–23]. Mature dI6 interneurons control alternating DOT1L participates in different protein complexes, hindlimb movement and coordination [24, 25]. The ven- which might explain its diverse functionalities [46] and trally generated interneuron classes integrate into loco- it is involved in specific forms of leukemia [47, 48]. It is motor networks, largely projecting on MNs [3]: different also indispensable for development [49], as loss of subsets of V0 participate in locomotion [26] and coordin- DOT1L is lethal at very early embryonic stages in the ation of left-right alternation [27], V1 and V2 contribute mouse [50]. DOT1L is fundamental for development of to limb articulation [28], and V3 to modulation of the diverse organs, as shown for example for cardiomyocytes locomotion rhythm [29]. The MNs, arising from a single differentiation [51] and functionality [52], erythropoiesis progenitor class, differentiate into a wide range of func- [53], and chondrogenesis [54]. Previous studies from our tionally diversified mature classes. MNs located in the laboratory highlighted that DOT1L activity plays import- spinal cord and brainstem are cholinergic and target a ant functional roles for CNS development. In the cere- variety of muscles [30]. bral cortex and cerebellum, but also in other somatic Both impaired neurulation and neurogenesis during organ systems, DOT1L balances progenitor proliferation spinal cord development lead to diverse pathologies. and differentiation [55–58]. Defects in neural tube fusion result in NTDs, which are We here report on our study aiming to explore the among the most common birth defects in human preg- role of DOT1L in neural tube development. Using nancies. The range of severity spans from lethal (anen- Wnt1-cre mediated conditional deletion of DOT1L in cephaly, craniorachischisis) to neurological handicaps the developing mouse neural tube, we here show that (open spina bifida) to asymptomatic conditions (closed in this model system DOT1L is not affecting neural spina bifida) [31]. Further, defective neurogenesis and tube closure, but that it is involved in correct differenti- patterning can lead to neuropathies [2]duetomal- ation of specific subsets of interneurons. Specifically, formed circuitry regarding touch [20], itch [32]and DOT1L contributes to the molecular specification of pain [33]. LHX2-expressing dI1 interneurons and migration of Both genetic and epigenetic factors have been studied the LHX9-expressing dI1 subset together with dI2, dI3, to identify the etiology of NTDs, especially since folate V0 and V1. deficiency has been indicated as a cofactor of NTD oc- currence [34]. Recent studies suggested that histone Materials and methods modifications such as acetylation or methylation corre- Mice lated with the occurrence of NTD in mouse or chick Wnt1-cre animals (Wnt1cre2 [59]) were mated with embryos [35–39]. Further, chromatin modifications have floxed
Load more

Recommended publications
  • Regular Article
    Regular Article MYELOID NEOPLASIA Potent inhibition of DOT1L as treatment of MLL-fusion leukemia Scott R. Daigle, Edward J. Olhava, Carly A. Therkelsen, Aravind Basavapathruni, Lei Jin, P. Ann Boriack-Sjodin, Christina J. Allain, Christine R. Klaus, Alejandra Raimondi, Margaret Porter Scott, Nigel J. Waters, Richard Chesworth, Mikel P. Moyer, Robert A. Copeland, Victoria M. Richon, and Roy M. Pollock Epizyme, Inc., Cambridge, MA Key Points Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there • EPZ-5676 is a potent DOT1L is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor inhibitor that causes tumor studies have demonstrated that the histone methyltransferase DOT1L is required for regressions in a rat xenograft the development and maintenance of MLL-rearranged leukemia in model systems. Here model of MLL-rearranged we describe the characterization of EPZ-5676, a potent and selective aminonucleoside leukemia. inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation.
    [Show full text]
  • The Histone Methyltransferase DOT1L Prevents Antigen-Independent
    bioRxiv preprint doi: https://doi.org/10.1101/826255; this version posted November 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells Eliza Mari Kwesi-Maliepaard1*, Muhammad Assad Aslam2,3*, Mir Farshid Alemdehy2*, Teun van den Brand4, Chelsea McLean1, Hanneke Vlaming1, Tibor van Welsem1, Tessy Korthout1, Cesare Lancini1, Sjoerd Hendriks1, Tomasz Ahrends5, Dieke van Dinther6, Joke M.M. den Haan6, Jannie Borst5, Elzo de Wit4, Fred van Leeuwen1,7,#, and Heinz Jacobs2,# 1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands 2Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands 3Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, 60800 Multan, Pakistan 4Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, and Oncode Institute, The Netherlands 5Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, and Oncode Institute, The Netherlands 6Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, 1081HV Amsterdam, The Netherlands 7Department of Medical Biology, Amsterdam UMC, location AMC, UvA, 1105 AZ Amsterdam, The Netherlands * These authors contributed equally to this work. # Equal contribution and corresponding authors [email protected]; [email protected] Lead contact: Fred van Leeuwen 1 bioRxiv preprint doi: https://doi.org/10.1101/826255; this version posted November 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Speed and Segmentation Control Mechanisms Characterized in Rhythmically- Active Circuits Created from Spinal Neurons Produced Fr
    RESEARCH ARTICLE Speed and segmentation control mechanisms characterized in rhythmically- active circuits created from spinal neurons produced from genetically-tagged embryonic stem cells Matthew J Sternfeld1,2, Christopher A Hinckley1, Niall J Moore1, Matthew T Pankratz1, Kathryn L Hilde1,3, Shawn P Driscoll1, Marito Hayashi1,2, Neal D Amin1,3,4, Dario Bonanomi1†, Wesley D Gifford1,4,5, Kamal Sharma6, Martyn Goulding7, Samuel L Pfaff1* 1Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States; 2Biological Sciences Graduate Program, University of California, San Diego, La Jolla, United States; 3Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, United States; 4Medical Scientist Training Program, University of California, San Diego, La Jolla, United States; 5Neurosciences Graduate Program, University of California, San Diego, La Jolla, United States; 6Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States; 7Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, United States *For correspondence: pfaff@salk. edu Abstract Flexible neural networks, such as the interconnected spinal neurons that control Present address: †Division of distinct motor actions, can switch their activity to produce different behaviors. Both excitatory (E) Neuroscience, San Raffaele and inhibitory (I) spinal neurons are necessary for motor behavior, but the influence of recruiting Scientific Institute, Milan, Italy different ratios of E-to-I cells remains unclear. We constructed synthetic microphysical neural networks, called circuitoids, using precise combinations of spinal neuron subtypes derived from Competing interests: The mouse stem cells. Circuitoids of purified excitatory interneurons were sufficient to generate authors declare that no oscillatory bursts with properties similar to in vivo central pattern generators.
    [Show full text]
  • Deconstructing Spinal Interneurons, One Cell Type at a Time Mariano Ignacio Gabitto
    Deconstructing spinal interneurons, one cell type at a time Mariano Ignacio Gabitto Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2016 © 2016 Mariano Ignacio Gabitto All rights reserved ABSTRACT Deconstructing spinal interneurons, one cell type at a time Mariano Ignacio Gabitto Abstract Documenting the extent of cellular diversity is a critical step in defining the functional organization of the nervous system. In this context, we sought to develop statistical methods capable of revealing underlying cellular diversity given incomplete data sampling - a common problem in biological systems, where complete descriptions of cellular characteristics are rarely available. We devised a sparse Bayesian framework that infers cell type diversity from partial or incomplete transcription factor expression data. This framework appropriately handles estimation uncertainty, can incorporate multiple cellular characteristics, and can be used to optimize experimental design. We applied this framework to characterize a cardinal inhibitory population in the spinal cord. Animals generate movement by engaging spinal circuits that direct precise sequences of muscle contraction, but the identity and organizational logic of local interneurons that lie at the core of these circuits remain unresolved. By using our Sparse Bayesian approach, we showed that V1 interneurons, a major inhibitory population that controls motor output, fractionate into diverse subsets on the basis of the expression of nineteen transcription factors. Transcriptionally defined subsets exhibit highly structured spatial distributions with mediolateral and dorsoventral positional biases. These distinctions in settling position are largely predictive of patterns of input from sensory and motor neurons, arguing that settling position is a determinant of inhibitory microcircuit organization.
    [Show full text]
  • MLL1 and DOT1L Cooperate with Meningioma-1 to Induce Acute Myeloid Leukemia
    RESEARCH ARTICLE The Journal of Clinical Investigation MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia Simone S. Riedel,1 Jessica N. Haladyna,1 Matthew Bezzant,1 Brett Stevens,2 Daniel A. Pollyea,2 Amit U. Sinha,3 Scott A. Armstrong,3 Qi Wei,4 Roy M. Pollock,5 Scott R. Daigle,5 Craig T. Jordan,2 Patricia Ernst,1 Tobias Neff,1 and Kathrin M. Bernt1 1Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, USA. 2Division of Hematology, University of Colorado Denver, Aurora, Colorado, USA. 3Division of Hematology/Oncology, Children’s Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. 4Department of Pathology, Children’s Hospital Colorado, Aurora, Colorado, USA. 5Epizyme Inc., Cambridge, Massachusetts, USA. Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either Mll1 or Dot1l in MN1-expressing cells abrogated the cell of origin– derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mll1 or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1hi leukemia, and human MN1hi/HOXA9hi leukemias were sensitive to pharmacologic inhibition of DOT1L.
    [Show full text]
  • Delineating the Diversity of Spinal Interneurons in Locomotor Circuits
    The Journal of Neuroscience, November 8, 2017 • 37(45):10835–10841 • 10835 Mini-Symposium Delineating the Diversity of Spinal Interneurons in Locomotor Circuits Simon Gosgnach,1 Jay B. Bikoff,2 XKimberly J. Dougherty,3 Abdeljabbar El Manira,4 XGuillermo M. Lanuza,5 and Ying Zhang6 1Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada, 2Department of Neuroscience, Columbia University, New York, New York 10032, 3Department of Neurobiology and Anatomy, Drexel University, Philadelphia, Pennsylvania 19129, 4Department of Neuroscience, Karolinska Institutet, Stockholm SE-171 77, Sweden, 5Department of Developmental Neurobiology, Fundacion Instituto Leloir, Buenos Aires C1405BWE, Argentina, and 6Department of Medical Neuroscience, Dalhousie University. Halifax, Nova Scotia B3H 4R2, Canada Locomotion is common to all animals and is essential for survival. Neural circuits located in the spinal cord have been shown to be necessary and sufficient for the generation and control of the basic locomotor rhythm by activating muscles on either side of the body in a specific sequence. Activity in these neural circuits determines the speed, gait pattern, and direction of movement, so the specific locomotor pattern generated relies on the diversity of the neurons within spinal locomotor circuits. Here, we review findings demon- strating that developmental genetics can be used to identify populations of neurons that comprise these circuits and focus on recent work indicating that many of these populations can be further subdivided
    [Show full text]
  • DOT1L Primarily Acts As a Transcriptional Repressor in Hematopoietic Progenitor Cells
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.15.341255; this version posted October 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. DOT1L primarily acts as a transcriptional repressor in hematopoietic progenitor cells Shaon Borosha1, Anamika Ratri1, Sami M. Housami1, Shubham Rai1, Subhra Ghosh1, Carrie A. Malcom1, V. Praveen Chakravarthi1, Jay L. Vivian1, Timothy A. Fields1, M.A. Karim Rumi1*, and Patrick E. Fields1*# 1Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS. *These authors contributed equally; #Corresponding author Short title: DOT1L regulated genes in the hematopoietic progenitors Keywords: DOT1L methyltransferase, mutant murine models, erythroid-myeloid progenitors, erythroid-myeloid differentiation. * Correspondence: Patrick E. Fields, Email: [email protected] Acknowledgements: This work was supported by the National Institutes of Health (R01DK091277). Disclosure: The authors do not have any conflicts of interest. bioRxiv preprint doi: https://doi.org/10.1101/2020.10.15.341255; this version posted October 16, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT DOT1L is essential for early hematopoiesis but the precise mechanisms remain largely unclear. The only known function of DOT1L is histone H3 lysine 79 (H3K79) methylation. We generated two mouse models; a Dot1L-knockout (Dot1L-KO), and another possessing a point mutation in its methyltransferase domain (Dot1L-MM) to determine the role of its catalytic activity during early hematopoiesis. We observed that Dot1L-KO embryos suffered from severe anemia, while Dot1L- MM embryos showed minimal to no anemia.
    [Show full text]
  • Regulation of Spinal Interneuron Development by the Olig-Related Protein Bhlhb5 and Notch Signaling Kaia Skaggs1,2, Donna M
    RESEARCH ARTICLE 3199 Development 138, 3199-3211 (2011) doi:10.1242/dev.057281 © 2011. Published by The Company of Biologists Ltd Regulation of spinal interneuron development by the Olig-related protein Bhlhb5 and Notch signaling Kaia Skaggs1,2, Donna M. Martin2,3 and Bennett G. Novitch1,2,4,* SUMMARY The neural circuits that control motor activities depend on the spatially and temporally ordered generation of distinct classes of spinal interneurons. Despite the importance of these interneurons, the mechanisms underlying their genesis are poorly understood. Here, we demonstrate that the Olig-related transcription factor Bhlhb5 (recently renamed Bhlhe22) plays two central roles in this process. Our findings suggest that Bhlhb5 repressor activity acts downstream of retinoid signaling and homeodomain proteins to promote the formation of dI6, V1 and V2 interneuron progenitors and their differentiated progeny. In addition, Bhlhb5 is required to organize the spatially restricted expression of the Notch ligands and Fringe proteins that both elicit the formation of the interneuron populations that arise adjacent to Bhlhb5+ cells and influence the global pattern of neuronal differentiation. Through these actions, Bhlhb5 helps transform the spatial information established by morphogen signaling into local cell-cell interactions associated with Notch signaling that control the progression of neurogenesis and extend neuronal diversity within the developing spinal cord. KEY WORDS: Neurogenesis, Interneurons, Neuronal fate, Notch signaling, Spinal cord, Transcription factors, Mouse, Chick INTRODUCTION V0-V3 interneurons and MNs (Briscoe and Ericson, 2001; Briscoe The control of vertebrate motor behaviors depends on spinal and Novitch, 2008). In the case of MN formation, the patterning interneuron circuits that relay sensory information from the actions of Shh and RA culminate in the expression of the bHLH periphery and modulate motor neuron (MN) activities.
    [Show full text]
  • Interneuron Diversity and Function in the Spinal Motor System
    Available online at www.sciencedirect.com ScienceDirect Interneuron diversity and function in the spinal motor system Jay B Bikoff Neural circuits in the spinal cord are the ultimate arbiters of generating patterned motor output, while integrating movement, serving as the conduit through which the rest of the sensory input and supraspinal information arriving nervous system controls muscle contraction to implement directly or indirectly from cortical, basal ganglia, brain- behavior. Over the last two decades, the genetic identity of stem, and cerebellar systems to enable animals to move in neurons in the spinal cord has come into view, revealing the a manner that meets their behavioral needs [4–6]. Reveal- richness of cellular diversity that underlies motor control. ing the identity, organization, and function of spinal Despite this progress, our understanding of how discrete types interneurons is, therefore, essential to understanding of spinal interneurons contribute to motor output remains the neural control of movement. tenuous. Here, I review the landscape of interneuron diversity in the spinal motor system, and highlight key challenges and Early studies of spinal interneuron organization largely novel approaches to linking the molecular and genetic focused on locomotion, one of the most fundamental taxonomy of spinal interneurons to functional aspects of motor functions in an animal’s behavioral repertoire. Over movement. a century ago, Thomas Graham Brown showed that neurons intrinsic to the spinal cord can generate rhythmic Address patterns of locomotor activity, establishing the concept of Department of Developmental Neurobiology, St. Jude Children’s central pattern generators and setting the stage for dec- Research Hospital, Memphis, TN, 38105, USA ades of work dissecting the components of these networks Corresponding author: Bikoff, Jay B ([email protected]) [7].
    [Show full text]
  • Activity of Spinal Interneurons and Their Effects on Forearm Muscles During Voluntary Wrist Movements in the Monkey
    Activity of Spinal Interneurons and Their Effects on Forearm Muscles During Voluntary Wrist Movements in the Monkey STEVE I. PERLMUTTER, MARC A. MAIER, AND EBERHARD E. FETZ Department of Physiology and Biophysics and Regional Primate Research Center, University of Washington, Seattle, Washington 98195 Perlmutter, Steve I., Marc A. Maier, and Eberhard E. Fetz. Dum and Strick 1996; Kuypers 1981; Ralston and Ralston Activity of spinal interneurons and their effects on forearm muscles 1985; Robinson et al. 1987). Spinal interneurons appear during voluntary wrist movements in the monkey. J. Neurophysiol. to integrate convergent supraspinal and peripheral afferent 80: 2475±2494, 1998. We studied the activity of 577 neurons in information and distribute appropriate signals to motoneu- the C6 ±T1 spinal cord of three awake macaque monkeys while they generated visually guided, isometric ¯exion/extension torques rons to activate muscles in coordinated patterns (Baldissera about the wrist. Spike-triggered averaging of electromyographic et al. 1981; Jankowska 1992). activity (EMG) identi®ed the units' correlational linkages with Although mammalian spinal pathways have been exam- °12 forearm muscles. One hundred interneurons produced changes ined extensively since Sherrington's re¯ex studies in the in the level of average postspike EMG with onset latencies consis- early 1900s (Sherrington 1910), virtually all physiological tent with mono- or oligosynaptic connections to motoneurons; investigations have been performed in anesthetized or re- these were classi®ed as premotor interneurons (PreM-INs). Most duced preparations. Of the few descriptions of interneuron PreM-INs (82%) produced postspike facilitations in forearm mus- properties in awake animals, most concern sensory responses cles. Earlier spike-related features, often beginning before the trig- (Bromberg and Fetz 1977; Cleland and Hoffer 1986; Collins ger spike, were seen in spike-triggered averages from 72 neurons.
    [Show full text]
  • A KMT2A-AFF1 Gene Regulatory Network Highlights the Role of Core Transcription Factors and Reveals the Regulatory Logic of Key Downstream Target Genes
    Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Research A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes Joe R. Harman,1,7 Ross Thorne,1,7 Max Jamilly,2 Marta Tapia,1,8 Nicholas T. Crump,1 Siobhan Rice,1,3 Ryan Beveridge,1,4 Edward Morrissey,5 Marella F.T.R. de Bruijn,1 Irene Roberts,3,6 Anindita Roy,3,6 Tudor A. Fulga,2,9 and Thomas A. Milne1,6 1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; 2MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; 3MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Department of Paediatrics, University of Oxford, Oxford, OX3 9DS, United Kingdom; 4Virus Screening Facility, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, United Kingdom; 5Center for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; 6NIHR Oxford Biomedical Research Centre Haematology Theme, University of Oxford, Oxford, OX3 9DS, United Kingdom Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) gene produce KMT2A fusion proteins such as KMT2A-AFF1 (previously MLL-AF4), caus- ing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs).
    [Show full text]
  • DOT1L Inhibition Is Lethal for Multiple Myeloma Due to Perturbation of the Endoplasmic Reticulum Stress Pathway
    www.oncotarget.com Oncotarget, 2020, Vol. 11, (No. 11), pp: 956-968 Research Paper DOT1L inhibition is lethal for multiple myeloma due to perturbation of the endoplasmic reticulum stress pathway Caroline Dafflon1, Swann Gaulis1, Louise Barys1, Karen Kapur2, Vanessa Cornacchione3, Lina Schukur1, Sebastian Bergling4, Elisabetta Traggiai3, Selina Jansky1, Leon Hellmann1, Barbara Schacher Engstler1, Grainne Kerr1, Antoine de Weck1, David A. Ruddy5, Ulrike Naumann6, Frédéric Stauffer7, Christoph Gaul7, Ying Lin8, Eric Billy1, Andreas Weiss1, Francesco Hofmann1, Moriko Ito1 and Ralph Tiedt1 1Novartis Institutes for BioMedical Research (NIBR) Oncology, Basel, Switzerland 2NIBR Informatics, Basel, Switzerland 3NIBR Biologics, Basel, Switzerland 4NIBR Chemical Biology and Therapeutics, Basel, Switzerland 5NIBR Oncology, Cambridge, MA, USA 6NIBR Analytical Sciences and Imaging, Basel, Switzerland 7NIBR Global Discovery Chemistry, Basel, Switzerland 8China Novartis Institutes for BioMedical Research, Shanghai, China Correspondence to: Ralph Tiedt, email: [email protected] Keywords: DOT1L; multiple myeloma; epigenetics; histone methylation; unfolded protein response Received: June 17, 2019 Accepted: January 29, 2020 Published: March 17, 2020 Copyright: Dafflon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The histone 3 lysine 79 (H3K79) methyltransferase (HMT) DOT1L is known to play a critical role for growth and survival of MLL-rearranged leukemia. Serendipitous observations during high-throughput drug screens indicated that the use of DOT1L inhibitors might be expandable to multiple myeloma (MM). Through pharmacologic and genetic experiments, we could validate that DOT1L is essential for growth and viability of a subset of MM cell lines, in line with a recent report from another team.
    [Show full text]