Regionally reduced brain volume, altered serotonin neurochemistry, and abnormal behavior in mice null for the circadian rhythm output gene Magel2

Magel2 belongs to the MAGE/necdin family of proteins, which have roles in cell cycle, differentiation, and apoptosis. The Magel2 gene is expressed in various brain regions, most notably the hypothalamus. Mice with a targeted deletion of Magel2 display hypoactivity, blunted circadian rhythm, decreased fertility, and increased adiposity. The human ortholog, MAGEL2, is one of a set of paternally expressed, imprinted genes inactivated in most cases of Prader–Willi syndrome, a complex neurodevelopmental disorder. To explore the role of Magel2, brain morphology, brain neurochemistry, and behavior were measured in Magel2‐null mice. Brain volume was reduced in specific regions, particularly in the parieto‐temporal lobe of the cerebral cortex, the amygdala, the hippocampus, and the nucleus accumbens, as measured by quantitative magnetic resonance imaging. Abnormal neurochemistry was detected in brain samples from adult mice, consisting of decreased serotonin and 5‐hydroxyindoleacetic acid in the cortex and the hypothalamus, and decreased dopamine in the hypothalamus. Magel2‐null mice displayed relatively normal motor and learning abilities, but exhibited abnormal behavior in novel environments. This study lends support to the important role of the circadian rhythm output gene Magel2 in brain structure and behavior. © 2009 Wiley‐Liss, Inc.

[1]  Jason P. Lerch,et al.  High Throughput Microimaging of the Mouse Brain , 2010 .

[2]  R. Wevrick,et al.  Loss of Magel2, a Candidate Gene for Features of Prader-Willi Syndrome, Impairs Reproductive Function in Mice , 2009, PloS one.

[3]  R. Mark Henkelman,et al.  High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice , 2008, NeuroImage.

[4]  R. Wevrick,et al.  Loss of the Prader‐Willi syndrome protein necdin causes defective migration, axonal outgrowth, and survival of embryonic sympathetic neurons , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[5]  Alan C. Evans,et al.  Cortical thickness measured from MRI in the YAC128 mouse model of Huntington's disease , 2008, NeuroImage.

[6]  Marwan Shinawi,et al.  Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster , 2008, Nature Genetics.

[7]  Jack W. Tsao,et al.  What's wrong with my mouse: Behavioral phenotyping of transgenic and knockout mice, J. Crawley. Wiley-Interscience, Hoboken, NJ (2007), 523 pages, $99.95 , 2008 .

[8]  J. Roder,et al.  Beta N‐acetylglucosaminyltransferase V (Mgat5) deficiency reduces the depression‐like phenotype in mice , 2008, Genes, brain, and behavior.

[9]  J. Crawley,et al.  Behavioral Phenotyping Strategies for Mutant Mice , 2008, Neuron.

[10]  U. Francke,et al.  SnoRNA Snord116 (Pwcr1/MBII-85) Deletion Causes Growth Deficiency and Hyperphagia in Mice , 2008, PloS one.

[11]  D. J. Driscoll,et al.  Pituitary abnormalities in Prader–Willi syndrome and early onset morbid obesity , 2008, American journal of medical genetics. Part A.

[12]  R. Kahn,et al.  Genes and structural brain imaging in schizophrenia , 2008, Current opinion in psychiatry.

[13]  M. Theodoro,et al.  Follicle stimulating and leutinizing hormones, estradiol and testosterone in Prader–Willi syndrome , 2008, American journal of medical genetics. Part A.

[14]  D. Amaral,et al.  Neuroanatomy of autism , 2008, Trends in Neurosciences.

[15]  A. Holland,et al.  The phenomenology and diagnosis of psychiatric illness in people with Prader–Willi syndrome , 2008, Psychological Medicine.

[16]  R. Mark Henkelman,et al.  Automated deformation analysis in the YAC128 Huntington disease mouse model , 2008, NeuroImage.

[17]  G. Grugni,et al.  Pituitary height and neuroradiological alterations in patients with Prader-Labhart-Willi syndrome , 2008, European Journal of Pediatrics.

[18]  J. Brosius,et al.  Deletion of the MBII-85 snoRNA Gene Cluster in Mice Results in Postnatal Growth Retardation , 2007, PLoS genetics.

[19]  C. Stewart,et al.  Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome. , 2007, Human molecular genetics.

[20]  M. P. Howell,et al.  The imprinted gene Magel2 regulates normal circadian output , 2007, Nature Genetics.

[21]  S. Hyman.  Neuroscience: Obsessed with grooming , 2007, Nature.

[22]  R. Henkelman,et al.  Mouse behavioral mutants have neuroimaging abnormalities , 2007, Human brain mapping.

[23]  John G. Sled,et al.  Behavioral Phenotypes of Disc1 Missense Mutations in Mice , 2007, Neuron.

[24]  R. Mark Henkelman,et al.  Sexual dimorphism revealed in the structure of the mouse brain using three-dimensional magnetic resonance imaging , 2007, NeuroImage.

[25]  M. Blue,et al.  Neonatal serotonin depletion alters behavioral responses to spatial change and novelty , 2007, Brain Research.

[26]  Jacqueline N. Crawley,et al.  What's Wrong With My Mouse? , 2007 .

[27]  D. J. Driscoll,et al.  Intracranial abnormalities detected by three‐dimensional magnetic resonance imaging in Prader–Willi syndrome , 2007, American journal of medical genetics. Part A.

[28]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[29]  A. Holland,et al.  The course and outcome of psychiatric illness in people with Prader-Willi syndrome: implications for management and treatment. , 2007, Journal of intellectual disability research : JIDR.

[30]  D. Murphy,et al.  Analyzing grooming microstructure in neurobehavioral experiments , 2007, Nature Protocols.

[31]  H. Meziane,et al.  Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death , 2006, BMC Developmental Biology.

[32]  M. Low,et al.  GH in the dwarf dopaminergic D2 receptor knockout mouse: somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin. , 2006, The Journal of endocrinology.

[33]  F Xavier Castellanos,et al.  Brain development and ADHD. , 2006, Clinical psychology review.

[34]  T. Nakada,et al.  Brain Developmental Abnormalities in Prader-Willi Syndrome Detected by Diffusion Tensor Imaging , 2006, Pediatrics.

[35]  Olivier Boss,et al.  Serotonin Reciprocally Regulates Melanocortin Neurons to Modulate Food Intake , 2006, Neuron.

[36]  B. Horsthemke,et al.  Imprinting defects on human chromosome 15 , 2006, Cytogenetic and Genome Research.

[37]  A. Toga,et al.  Mapping brain maturation , 2006, Trends in Neurosciences.

[38]  J. Michael Tyszka,et al.  Statistical diffusion tensor histology reveals regional dysmyelination effects in the shiverer mouse mutant , 2006, NeuroImage.

[39]  R Mark Henkelman,et al.  Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography. , 2006, Physiological genomics.

[40]  R. Deacon,et al.  Digging and marble burying in mice: simple methods for in vivo identification of biological impacts , 2006, Nature Protocols.

[41]  J. Roder,et al.  Effects of the rd1 Mutation and Host Strain on Hippocampal Learning in Mice , 2005, Behavior genetics.

[42]  J. Greer,et al.  Developmental abnormalities of neuronal structure and function in prenatal mice lacking the prader-willi syndrome gene necdin. , 2005, The American journal of pathology.

[43]  Carolyn C. Meltzer,et al.  Serotonin alterations in anorexia and bulimia nervosa: New insights from imaging studies , 2005, Physiology & Behavior.

[44]  U. Francke,et al.  Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15)(q27;q11.2) associated with Prader-Willi syndrome , 2005, BMC Medical Genetics.

[45]  Alan C. Evans,et al.  A three-dimensional MRI atlas of the mouse brain with estimates of the average and variability. , 2005, Cerebral cortex.

[46]  R. Wevrick,et al.  Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth. , 2005, Human molecular genetics.

[47]  Pierre van der Bruggen,et al.  Structure, chromosomal localization, and expression of 12 genes of the MAGE family , 2005, Immunogenetics.

[48]  S. Taneja,et al.  MR of the pituitary in patients with Prader-Willi syndrome: Size determination and imaging findings , 2005, Pediatric Radiology.

[49]  Stuart Maudsley,et al.  A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin , 2004, Ageing Research Reviews.

[50]  Richard G M Morris,et al.  Festina lente: Late-night thoughts on high-throughput screening of mouse behavior , 2004, Nature Neuroscience.

[51]  R. Stackman,et al.  On the delay-dependent involvement of the hippocampus in object recognition memory , 2004, Neurobiology of Learning and Memory.

[52]  K. Devriendt,et al.  Psychotic disorders in Prader–Willi syndrome , 2004, American journal of medical genetics. Part A.

[53]  E. Nestler,et al.  Neurobehavioral assessment in the information age , 2004, Nature Neuroscience.

[54]  Anthony P. Goldstone,et al.  Prader-Willi syndrome: advances in genetics, pathophysiology and treatment , 2004, Trends in Endocrinology & Metabolism.

[55]  K. Yoshikawa,et al.  Necdin-related MAGE Proteins Differentially Interact with the E2F1 Transcription Factor and the p75 Neurotrophin Receptor* , 2004, Journal of Biological Chemistry.

[56]  U. Eiholzer,et al.  A Comprehensive Team Approach to the Management of Patients with Prader-Willi Syndrome , 2004, Journal of pediatric endocrinology & metabolism : JPEM.

[57]  P. Gaspar,et al.  The developmental role of serotonin: news from mouse molecular genetics , 2003, Nature Reviews Neuroscience.

[58]  R. Wevrick,et al.  Prader-Willi syndrome transcripts are expressed in phenotypically significant regions of the developing mouse brain. , 2003, Gene expression patterns : GEP.

[59]  J. Greer,et al.  Absence of Ndn, Encoding the Prader-Willi Syndrome-Deleted Gene necdin, Results in Congenital Deficiency of Central Respiratory Drive in Neonatal Mice , 2003, The Journal of Neuroscience.

[60]  E. Arenas,et al.  The p75 Neurotrophin Receptor Interacts with Multiple MAGE Proteins* , 2002, The Journal of Biological Chemistry.

[61]  K. Yoshikawa,et al.  Necdin is required for terminal differentiation and survival of primary dorsal root ganglion neurons. , 2002, Experimental cell research.

[62]  R. Leak,et al.  Suprachiasmatic nucleus organization , 2002, Cell and Tissue Research.

[63]  Thomas E. Nichols,et al.  Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate , 2002, NeuroImage.

[64]  P. Barker,et al.  The MAGE proteins: Emerging roles in cell cycle progression, apoptosis, and neurogenetic disease , 2002, Journal of neuroscience research.

[65]  C. Morris,et al.  Behavioral phenotypes in genetic syndromes: genetic clues to human behavior. , 2002, Advances in pediatrics.

[66]  Jocelyn M. Bischof,et al.  A necdin/MAGE-like gene in the chromosome 15 autism susceptibility region: expression, imprinting, and mapping of the human and mouse orthologues , 2001, BMC Genetics.

[67]  S. Schwartz,et al.  The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. , 2001, Pediatrics.

[68]  M. Bertrand,et al.  An overview of the MAGE gene family with the identification of all human members of the family. , 2001, Cancer research.

[69]  R. Ekman,et al.  ‘Cerebrospinal fluid neuropeptide Y in Prader‐Willi syndrome’ , 2001, Developmental medicine and child neurology.

[70]  F. Vaccarino,et al.  Analysis of amino acids and catecholamines, 5-hydroxytryptamine and their metabolites in brain areas in the rat using in vivo microdialysis. , 2001, Methods.

[71]  D. Abrous,et al.  Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. , 2000, Human molecular genetics.

[72]  Philippe P Roux,et al.  NRAGE, A Novel MAGE Protein, Interacts with the p75 Neurotrophin Receptor and Facilitates Nerve Growth Factor–Dependent Apoptosis , 2000, Neuron.

[73]  Stormy J. Chamberlain,et al.  Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype. , 2000, Human molecular genetics.

[74]  F. Watrin,et al.  The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region. , 1999, Human molecular genetics.

[75]  S. Kiebel,et al.  Detecting Structural Changes in Whole Brain Based on Nonlinear Deformations—Application to Schizophrenia Research , 1999, NeuroImage.

[76]  P. Chomez,et al.  A new family of mouse genes homologous to the human MAGE genes. , 1999, Genomics.

[77]  C. Gillberg,et al.  Cerebrospinal fluid monoamines in Prader–Willi syndrome , 1998, Biological Psychiatry.

[78]  J. Månsson,et al.  Is monoamine oxidase activity elevated in Prader-Willi syndrome? , 1998, European Child & Adolescent Psychiatry.

[79]  E. Fisher,et al.  Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment , 1997, Mammalian Genome.

[80]  O. de Backer,et al.  Structure, chromosomal location, and expression pattern of three mouse genes homologous to the human MAGE genes. , 1995, Genomics.

[81]  D. Collins,et al.  Automatic 3D Intersubject Registration of MR Volumetric Data in Standardized Talairach Space , 1994, Journal of computer assisted tomography.

[82]  K. Yoshikawa,et al.  A novel brain-specific mRNA encoding nuclear protein (necdin) expressed in neurally differentiated embryonal carcinoma cells. , 1991, Biochemical and biophysical research communications.