• Goldowitz, Daniel

    Titles
    Investigator, BC Children's Hospital

    Senior Scientist, Centre for Molecular Medicine and Therapeutics 
    Professor, Department of Medical Genetics, University of British Columbia
    Canada Research Chair, Tier 1

    Degrees / Designations
    BA, PhD
    Primary Area of Research
    Brain, Behaviour & Development
    Secondary Area(s) of Research
    Phone
    604-875-3822
    Fax
    604-875-3840
    Lab Phone
    604-875-5259
    Assistant
    Anita Sham
    Assistant Phone
    604-875-3827
    Mailing Address

    BC Children's Hospital Research Institute
    Room 2026
    950 West 28th Avenue
    Vancouver, BC V5Z 4H4

    Affiliate Websites
    Research Areas
    • The role of genes in the development of the normal and abnormal central nervous system
    • Cell migration
    • Cerebellum
    • Mouse
    • Autism
    Summary

    One of the most daunting problems of modem biology is to determine how a genome consisting of only ~30,000 genes drives the development of one of the most complex of organ systems – the mammalian brain. Most of the time – amazingly – the brain develops perfectly. When cells do not follow the proper developmental pathways, it leads to disorders of the developing central nervous system (CNS). These developmental brain disorders can have a clear genetic basis (e.g. forms of mental retardation and lissencephaly) or a far more complex etiology that involves multiple genes and environmental factors (e.g. autism, attention deficit disorder and schizophrenia).

    The lab studies both single gene and more complex developmental disorders of the CNS. The research integrates the power of genomics, informatics and the mouse as an experimental model system to drive discovery about normal and abnormal brain development and to identify new therapies and interventions to improve outcomes for affected children.

    Current Projects

    My focus is on the cerebellum, a brain region involved in numerous levels of basic and higher function, and associated with developmental and behavioural disorders (eg, autism, ADHD, schizophrenia). My strength is in approaching neurodevelopment through the lens of genetics to (i) discover and validate genes involved in cerebellar development; (ii) create mouse models of perturbed cerebellar function to identify the earliest diagnostic signs of the disorder and develop evidence-based interventions; and (iii) understand the role of complex genetics, such as gene-environment interactions, in cerebellar development.

    Novel genes involved in cerebellar development: discovery & validation
    We use two large databases that we have built (www.cbgrits.org) or contributed to (fantom.gsc.riken.jp) that have painted a relatively complete transcriptome landscape of the cerebellum over developmental time and discover new genes and their relationship to other genes and gene pathways. We will validate the role of these genes in cerebellar development using techniques such as siRNA knockdown, genetically engineered knockouts and experimental chimeras.

    Mouse models for understanding neurodevelopmental disorders and interventions
    We have 4 projects at various stages that have been designed to examine neurodevelopmental disorders: the loss of Purkinje cells in autism (one of the few documented neuroanatomic hallmarks of autism), a sequelae of extreme prematurity, intraventricular haemorrhage (IVH), and more recently, a mouse model for intrauterine growth restriction (IUGR) which is associated with adverse outcomes in humans; and a mouse model for brain insults coupled with inflammatory challenges that are risk factors in prematurity.

    Gene-environment interactions in cerebellar development and function: insights into the origins of complex brain disorders
    Fetal and perinatal events such as growth restriction and extreme prematurity exert a system-wide effect and falls under the framework of the developmental origins of health and disease. Our work will identify key transcriptomic and epigenomic changes that will suggest targets for intervention. We have used this approach with IVH and our initial work with IUGR. With the IUGR, we saw that the cerebellar epigenome had alterations in methylation. Treatment of the IUGR mice with a methyl-donor rich diet ameliorated the cerebellar phenotype and function of the IUGR pups, as well as altered the epigenome.

    Selected Publications

    THOMAS HA, Douglas Swanson, MATT LAROUCHE, Dave Weeden, Kristin Hamre, Michael Langston, Charles Phillips, Mingzhou Song, Zhengyu Ouyang, Elissa Chesler, Suman Duvvurru, Roumyana Yordanova, Yan Cui, Kate Campbell, Greg Ricker, Carey Phillips, Ramin Homayouni, Daniel Goldowitz. (2015). CbGRiTS: Cerebellar Gene Regulation in Time and Space. Developmental Biology. 397(1): 18-30. PMID: 25446528.

    JOANNA YEUNG, THOMAS HA, Douglas Swanson, Kunho Choi, Yiai Tong and Dan Goldowitz. (2014). Wls provides a new compartmental view of the rhombic lip in mouse cerebellar development. The Journal of Neuroscience. 34(37): 12527-12537. PMID: 25209290.

    Forrest AR....Goldowitz D,....HA TJ, ....ZHANG PG..Hayashizaki Y. (2014). A promoter-level mammalian expression atlas. Nature.507(7493): 462-470. PMID:24670764.

    YOO JY, MAK GK, Goldowitz D. (2014). The effect of hemorrhage on the development of the postnatal mouse cerebellum. Experimental Neurology. 252: 85-94. PMID: 24252180.

    HA TJ, Swanson DJ , Kirova R , YEUNG J , Choi K , Tong Y , Chesler EJ , Goldowitz D. (2012). Genome-wide microarray comparison reveals downstream genes of Pax6 in the developing mouse cerebellum. The European Journal of Neuroscience. 36(7): 2888-2898. PMID:22817342

    Tong Y , HA TJ , Liu L , Nishimoto A , Reiner A , Goldowitz D. (2011). Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development. The Journal of Neuroscience. 31(41): 14794-14799. PMID: 21994396.

    Martin LA , Goldowitz D , Mittleman G. (2010). Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism. The European Journal of Neuroscience. 31(3): 544-555. PMID: 20105240.

    Bult C , Kibbe WA , Snoddy J , Vitaterna M , Swanson D , Pretel S , Li Y , Hohman MM , Rinchik E , Takahashi JS , Frankel WN , Goldowitz D. (2004). A genome end-game: understanding gene function in the nervous system. Nature Neuroscience. 7(5): 484-5. PMID: 15114363.

    Goldowitz D , Hamre KM , Przyborski SA , Ackerman SL. (2000). Granule cells and cerebellar boundaries: analysis of Unc5h3 mutant chimeras. The Journal of Neuroscience. 20(11): 4129-37. PMID: 10818148.

    Goldowitz D , HAMRE K. (1998). The cells and molecules that make a cerebellum. Trends in Neurosciences. 21(9): 375-82. PMID: 9735945.

    Grants
    Honours & Awards

    Scientific Director, NeuroDevNet NCE, 2009 – current

    Canadian Research Chair in Developmental Neurogenetics Tier 1, 2007 - 2021

    University of Florida, Applebaum Professorship, 2009

    Associate Editor, Genes, Brain and Behavior Editorial Board, Cerebellum

    Serves as External Advisor: Kectucky Biomedical Research Infrastructure Network, The Urban Child Institute (Memphis), Community Works (Calgary), The John Merck Fund

    Research Group Members
    • Anita Sham, Research Manager
    • Joanna Yeung, PhD student
    • Peter Zhang, PhD student
    • Sophie Tremblay, PhD student