Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration

Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied—the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.

[1]  D. J. Peterson,et al.  Sleep Behavior and EEG Oscillations in Aged Dp(16)1Yey/+ Mice: A Down Syndrome Model , 2018, Neuroscience.

[2]  Stylianos E. Antonarakis,et al.  Down syndrome and the complexity of genome dosage imbalance , 2016, Nature Reviews Genetics.

[3]  J. Delabar,et al.  Specific age-related molecular alterations in the cerebellum of Down syndrome mouse models , 2016, Brain Research.

[4]  S. McMahon,et al.  Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury , 2016, Brain : a journal of neurology.

[5]  V. Tybulewicz,et al.  Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel , 2015, eLife.

[6]  Y. Hérault,et al.  Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models , 2015, Front. Behav. Neurosci..

[7]  E. Mojs,et al.  Delays in Motor Development in Children with Down Syndrome , 2015, Medical science monitor : international medical journal of experimental and clinical research.

[8]  H. Moriya,et al.  Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes , 2015, Genes & development.

[9]  Mara Dierssen,et al.  Opposite Phenotypes of Muscle Strength and Locomotor Function in Mouse Models of Partial Trisomy and Monosomy 21 for the Proximal Hspa13-App Region , 2015, PLoS genetics.

[10]  Y. Hérault,et al.  Dosage of the Abcg1-U2af1 Region Modifies Locomotor and Cognitive Deficits Observed in the Tc1 Mouse Model of Down Syndrome , 2015, PloS one.

[11]  Y. Yanagawa,et al.  Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage , 2014, Neurobiology of Disease.

[12]  J. Richtsmeier,et al.  Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice , 2014, American journal of medical genetics. Part A.

[13]  Kai Rothkamm,et al.  Massively Parallel Sequencing Reveals the Complex Structure of an Irradiated Human Chromosome on a Mouse Background in the Tc1 Model of Down Syndrome , 2013, PloS one.

[14]  M. Dierssen,et al.  Dyrk1A Is Dynamically Expressed on Subsets of Motor Neurons and in the Neuromuscular Junction: Possible Role in Down Syndrome , 2013, PloS one.

[15]  A. Amon,et al.  Aneuploidy causes proteotoxic stress in yeast. , 2012, Genes & development.

[16]  M. Dierssen.  Down syndrome: the brain in trisomic mode , 2012, Nature Reviews Neuroscience.

[17]  Y. Hérault,et al.  Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling down syndrome , 2011, Mammalian Genome.

[18]  V. Tybulewicz,et al.  Down syndrome: searching for the genetic culprits , 2011, Disease Models & Mechanisms.

[19]  B. Kalmar,et al.  A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis , 2011, Disease Models & Mechanisms.

[20]  George Stoica,et al.  A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. , 2010, Human molecular genetics.

[21]  D. Andersson,et al.  The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity , 2010, Molecular pain.

[22]  Y. Hérault,et al.  A new mouse model for the trisomy of the Abcg1–U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome , 2009, Human molecular genetics.

[23]  David J Anderson,et al.  Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli , 2009, Proceedings of the National Academy of Sciences.

[24]  Elizabeth M.C. Fisher,et al.  Impairments in motor coordination without major changes in cerebellar plasticity in the Tc1 mouse model of Down syndrome , 2009, Human molecular genetics.

[25]  T. Yaksh,et al.  Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death , 2008, Proceedings of the National Academy of Sciences.

[26]  P. Vaccaro,et al.  Measurements of neuromuscular tone and strength in Down's syndrome children. , 2008, Journal of mental deficiency research.

[27]  K. Millen,et al.  Proprioceptive Sensory Neuropathy in Mice with a Mutation in the Cytoplasmic Dynein Heavy Chain 1 Gene , 2007, The Journal of Neuroscience.

[28]  Marie-Claude Potier,et al.  Down syndrome gene dosage imbalance on cerebellum development , 2007, Progress in Neurobiology.

[29]  N. Nowak,et al.  Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities. , 2007, Human molecular genetics.

[30]  P. Beachy,et al.  Defective cerebellar response to mitogenic Hedgehog signaling in Down's syndrome mice , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Dean Nizetic,et al.  An Aneuploid Mouse Strain Carrying Human Chromosome 21 with Down Syndrome Phenotypes , 2005, Science.

[32]  Stylianos E. Antonarakis,et al.  Chromosome 21 and Down syndrome: from genomics to pathophysiology , 2004, Nature Reviews Genetics.

[33]  X. Estivill,et al.  Motor phenotypic alterations in TgDyrk1a transgenic mice implicate DYRK1A in Down syndrome motor dysfunction , 2004, Neurobiology of Disease.

[34]  X. Estivill,et al.  Dyrk1A Haploinsufficiency Affects Viability and Causes Developmental Delay and Abnormal Brain Morphology in Mice , 2002, Molecular and Cellular Biology.

[35]  X. Estivill,et al.  Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. , 2001, Human molecular genetics.

[36]  J T Richtsmeier,et al.  Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. , 2000, Human molecular genetics.

[37]  A. Jobling.  Motor development in school-aged children with Down Syndrome , 1998 .

[38]  C. Epstein,et al.  Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. McMahon,et al.  Tackling Pain at the Source: New Ideas about Nociceptors , 1998, Neuron.

[40]  R. Bronson,et al.  A mouse model for Down syndrome exhibits learning and behaviour deficits , 1995, Nature Genetics.

[41]  T. Yaksh,et al.  Quantitative assessment of tactile allodynia in the rat paw , 1994, Journal of Neuroscience Methods.

[42]  R. Dubner,et al.  A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia , 1987, Pain.

[43]  M. Woollacott,et al.  Dynamics of postural control in the child with Down syndrome. , 1985, Physical therapy.

[44]  N. A. Rocha,et al.  Motor Performance of Children With Down Syndrome and Typical Development at 2 to 4 and 26 Months , 2015, Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association.

[45]  E Mercuri,et al.  Motor and perceptual-motor competence in children with Down syndrome: variation in performance with age. , 1999, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[46]  M. Davisson,et al.  Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. , 1990, Progress in clinical and biological research.

[47]  H. Creasey,et al.  Neurophysiological evidence of aging in Down's syndrome. , 1983, Clinical and experimental neurology.

[48]  J. McPherson,et al.  A Chromosome 21 Critical Region Does Not Cause Specific Down Syndrome Phenotypes , 2022 .