Our laboratory uses mouse mutants and experimental embryology and reference populations to study how single genes, or ensembles of genes, participate to support the normal development and function of the central nervous system.
The cerebellum is emerging as an important brain region for the coordination of motor and cognitive behaviors. Developmental abnormalities of the cerebellum have been linked to autism, schizophrenia, and other disorders of human neural function. This grant proposes to acquire extensive new data sets for gene expression and cellular phenotypes over six epochs of cerebellar development in over 30 recombinant inbred (RI) strains of mice (BXD) and 15 single gene mutant mice. This data will be web-accessible via WebQTL. We will also develop and integrate web-based informatic and visualization tools for researchers to analyze our data sets, provide datasets of their own for analysis, and test hypotheses about the cellular and molecular development of the cerebellum.
Four specific aims are proposed that will be supported by four core functions.
We will obtain the phenotypic data on the full spectrum of expressed genes and several quantifiable developmental processes in RI and mutant mice. This data will be integrated into a current database that houses an exceptional array of phenotypic data on the adult mouse brain, WebQTL.
We will use WebQTL, Bayesian method analysis, graph theoretical approaches to the identification of cliques in expression data, and latent semantic indexing of Medline references to mine data on the patterns, both in time and space, of expressed genes and cellular phenotypes.
We will use molecular(qRT-PCR), anatomical (in situ hybridization and immunocytochemistry) and experimental (siRNA) approaches to validate inferences about gene and phenotype relationships.
Finally, we will develop a web-accessible, 3D, high-end animation of the developing cerebellum that will be used for heuristic and experimental purposes.
The data that is obtained and the tools that are constructed in this project will be fully open to the research community. This project is also designed to interface with several of the currently funded Human Brain Projects that look at the anatomy and cell biology of the adult mouse brain and cerebellum. The phenotypic data that is gathered will contribute to the growing understanding of the molecular and cellular bases of cerebellar development. Such information may help understand and treat disorders of cerebellar origin, such as the most common form of childhood brain cancer, the medullablastoma, which is believed to emanate from the developing granule cells of the cerebellum. In the long term, we hope to use the tools developed in this project to make predictions about the molecular pathways and cellular programs that are important to the well-being of the central nervous system.
One key limitation to our understanding of autism is the limited access to studying developmental events in the human brain. The use of model organisms that have homologous genetic and anatomical underpinnings is critical. The mouse is recognized as the leader in “pre-clinical” models and our research employs a unique genetic and developmental model of brain pathology that is known to underlie autism to gain insights into the etiology of autism and serve as a platform to test interventional strategies. Our work proposes to use a mouse model that has varying losses of cerebellar Purkinje cells to model the role of this structure in behaviors that are “autistic-like” and explore hypotheses about how those losses affect the function of the CNS at the behavioral and anatomical levels. This systems approach should present researchers with a new understanding of cerebellar function and connectivity with the prefrontal cortex and the possible relationships this has with modeling autistic-like behaviors. We use a mutant mouse, Lurcher, that loses all of its Purkinje cells over the 2-3 weeks of life, akin to the last trimester and perinatal period in the human. By making experimental mouse chimeras with Lurcher and wildtype mice (the joining together of 8 cell embryos to make an organisms with cells from both genotypes), we produce mice that have varying percentages of Lurcher and wildtype cells, and hence varying numbers of Purkinje cells as the Lurcher mutation principly affects these cells. Behavioral and anatomical analyses of these chimeras are made to understand the relationship between a primary loss of Purkinje neurons to behavior and connectivity between the cerebellum and other key structures which are believed to underlie the autistic disorder.
Experimental mouse chimeras will be used in the analysis of the cellular target of neurodegenerative diseases. The well-documented strain differences in mice to kainic acid neurotoxicity will be used as the test-bed for this approach. C57BL/6 and FVB/N mice are remarkably resistant and sensitive, respectively, to the neurotoxic effects of kainic acid. In these experiments we will aggregate embryos from these two lines of mice to examine whether neuron-intrinsic or neuron-extrinsic mechanisms are responsible for the death of neurons in the hippocampal formation. The key to the analysis is the recent availability of genetic markers that are histologically demonstrable within cells of each of these strains. Control and C57BL/6-ROSA26 <--> FVB/N-GFP chimeric mice will be injected with kainic acid for 2 and 7 day survival. Sections of the fixed brains will be processed for the histological demonstration of cell genotype and cell phenotype (alive or dying). Three avenues of investigation will be pursued. First, it will be determined if a linear relationship exists between the number of living neurons and percentage of chimerism. Second, the non-neuronal cell populations (glia and endothelial cells) of chimeras will be examined to determine if the percentage chimerism of these cells exhibit any relationship to phenotypic outcome. Finally, the genotypic origin of non-neuronal cells in the vicinity of affected or unaffected hippocampal neurons will be examined for further evidence for a cell-intrinsic or –extrinsic explanation. The long term goal of this research is to establish a powerful approach to the analysis of the cellular targets of human neurodegenerative diseases modeled in the mouse. This will provide important insights for a rationally-based therapy for a variety of neurological diseases such as Parkinson’s, stroke, and epilepsy.
Dickson PE, Corkill B, McKimm E, Miller MM, Calton MA, Goldowitz D, Blaha CD, Mittleman G. Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome. Behav Brain Res. 252:126-35. 2013.
Goldowitz D. Excessive activation of tissue plasminogen activator makes a mouse nervous. Proc Natl Acad Sci U S A. 110(27):10882-3. 2013.
Rogers TD, McKimm E, Dickson PE, Goldowitz D, Blaha CD, Mittleman G. Is autism a disease of the cerebellum? An integration of clinical and pre-clinical research. Front Syst Neurosci.7:15. 2013.
Rogers TD, Dickson PE, McKimm E, Heck DH, Goldowitz D, Blaha CD, Mittleman G. Reorganization of Circuits Underlying Cerebellar Modulation of Prefrontal Cortical Dopamine in Mouse Models of Autism Spectrum Disorder. Cerebellum. 12(4):547-56. 2013.
Yoo JY, Larouche M, Goldowitz D. The Expression of HDAC1 and HDAC2 During Cerebellar Cortical Development. Cerebellum. 12(4):534-46. 2013.
Poon A, Goldowitz D. Effects of age and strain on cell proliferation in the mouse rostral migratory stream. Neurobiol Aging. 34(6):1712.e15-21. 2013.
Dubose CS, Chesler EJ, Goldowitz D, Hamre KM. Use of the Expanded Panel of BXD Mice Narrow QTL Regions in Ethanol-Induced Locomotor Activation and Motor Incoordination. Alcohol Clin Exp Res. 37(1):170-83. 2013.
Qiao S, Kim SH, Heck D, Goldowitz D, Ledoux MS, Homayouni R. Dab2IP GTPase Activating Protein Regulates Dendrite Development and Synapse Number in Cerebellum. PLoS One. 8(1). 2013.
Ha TJ, Swanson DJ, Kirova R, Yeung J, Choi K, Tong Y, Chesler EJ, Goldowitz D. Genome-wide microarray comparison reveals downstream genes of Pax6 in the developing mouse cerebellum. Eur J Neurosci. 36(7):2888-98. 2012.
Liu L, Hamre KM, Goldowitz D. Kainic acid-induced neuronal degeneration in hippocampal pyramidal neurons is driven by both intrinsic and extrinsic factors: analysis of FVB/N?C57BL/6 chimeras. J Neurosci. 32(35):12093-101. 2012.
Lehman AM, du Souich C, Chai D, Eydoux P, Huang JL, Fok AK, Avila L, Swingland J, Delaney AD, McGillivray B, Goldowitz D, Argiropoulos B, Kobor MS, Boerkoel CF. 19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression. Clin Genet. 81(1):56-63. 2012.
Fatemi SH, Aldinger KA, Ashwood P, Bauman ML, Blaha CD, Blatt GJ, Chauhan A, Chauhan V, Dager SR, Dickson PE, Estes AM, Goldowitz D, Heck DH, Kemper TL, King BH, Martin LA, Millen KJ, Mittleman G, Mosconi MW, Persico AM, Sweeney JA, Webb SJ, Welsh JP. Consensus Paper: Pathological Role of the Cerebellum in Autism. Cerebellum. 11(3):777-807. 2012
Goldowitz D. Linking early brain and biological development to psychiatry. J Can Acad Child Adolesc Psychiatry. 20(4):252. 2011.
Tong Y, Ha TJ, Liu L, Nishimoto A, Reiner A, Goldowitz D. Spatial and Temporal Requirements for huntingtin (Htt) in Neuronal Migration and Survival during Brain Development. J Neurosci. 31(41):14794-9. 2011.
Ouyang Z, Song M, Gueth R, Ha TJ, Larouche M, Goldowitz D. Conserved and differential gene interactions in dynamical biological systems. Bioinformatics. 27(20):2851-8, 2011.
Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: Neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse. 65(11):1204-12, 2011.
Di Curzio DL, Goldowitz D. The genetic basis of adrenal gland weight and structure in BXD recombinant inbred mice. Mamm. Genome 22(3-4):209-34. (2011)
Swanson DJ, Goldowitz D. Experimental Sey mouse chimeras reveal the developmental deficiencies of Pax6-null granule cells in the postnatal cerebellum.Dev. Biol. 351(1):1-12. (2011)
Mittleman G, Call SB, Cockroft JL, Goldowitz D, Matthews DB, Blaha CD. Dopamine dynamics associated with, and resulting from, schedule-induced alcohol self-administration: analyses in dopamine transporter knockout mice. (2011)
Dickson PE, Rogers TD, Lester DB, Miller MM, Matta SG, Chesler EJ, Goldowitz D, Blaha CD, Mittleman G. Genotype-dependent effects of adolescent nicotine exposure on dopamine functional dynamics in the nucleus accumbens shell in male and female mice: a potential mechanism underlying the gateway effect of nicotine. (2011)
Lehman A, du Souich C, Chai D, Eydoux P, Huang J, Fok A, Avila L, Swingland J, Delaney A, McGillivray B, Goldowitz D, Argiropoulos B, Kobor M, Boerkoel C. 19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression. (2010)
Swanson DJ, Steshina EY, Wakenight P, Aldinger KA, Goldowitz D, Millen KJ, Chizhikov VV. Phenotypic and genetic analysis of the cerebellar mutant tmgc26, a new ENU-induced ROR-alpha allele. Eur. J. Neurosci. 32(5):707-16. (2010)
Samaan G, Yugo D, Rajagopalan S, Wall J, Donnell R, Goldowitz D, Gopalakrishnan R, Venkatachalam S. Foxn3 is essential for craniofacial development in mice and a putative candidate involved in human congenital craniofacial defects. Biochem. Biophys. Res. Commun. 400(1):60-5. (2010)
Fyfe JC, Al-Tamimi RA, Castellani RJ, Rosenstein D, Goldowitz D, Henthorn PS.Inherited neuroaxonal dystrophy in dogs causing lethal, fetal-onset motor system dysfunction and cerebellar hypoplasia. J. Comp. Neurol. 518(18):3771-84. (2010)
Scientific Director, NeuroDevNet (funded by Networks of Centres of Excellence): 2009 ~ 2014
President, International Behavioural and Neural Genetics Society: 2007
Canadian Research Council Chair in Developmental Neurogenetics: 2007 - present