One of the most daunting problems of modem biology is to determine how a genome consisting of only ~30,OOO 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, infonnatics 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.

The genetic bases of neural development
This research will have two objectives: (a) Deciphering the genome-wide architecture of cerebellar development and (b) Discovery-based analysis of single gene mutations that affect cerebellar development. We use bioinformatics and quantitative trait analysis of micro array expression and neuroanatomical endpoints over developmental time to get at these objectives.

The role of the Huntington's gene (Hdh) in neural development
An expanded trinucleotide repeat in the HD gene leads to expression of a mutant huntingtin protein (Hdh) that causes devastation of the nervous system. Some of the most exciting active therapeutic strategies being pursued in Huntington's disease (HD) are approaches that eliminate or decrease Hdh expression. To better understand the biologic implications of these therapeutic strategies it is critical to investigate the functional role that huntingtin normally plays in CNS development. Knockdown of Hdh during embryonic development in the mouse, using shRNA, and engineered mouse lines will be the tools to explore this issue.

Systems neurobiology of autism
Autism is a complex syndrome that has a clear developmental basis and good possibilities for intervention. The cerebellum has been implicated in the etiology of autism. Our work is to determine the relationship between the number of Purkinje cells and cerebellar connectivity to the Prefrontal Cortex using in vivo electrochemistry, neurophysiology, and anatomy and how those parameters mediate the autism-related phenotypes. We use experimental mouse chimeras in this work.

Yang GS, Banks KG, Bonaguro RJ, Wilson G, Dreolini L, de Leeuw CN, Liu L, Swanson DJ, Goldowitz D, Holt RA, Simpson EM.: Next generation tools for high-throughput promoter and expression analysis employing single-copy knock-ins at the Hprt1 locus. Genomics. 2009 Mar;93(3):196-204.

Dragatsis I, Goldowitz D, Del Mar N, Deng Y, Meade CA, Liu L, Sun Z, Dietrich P, Yue J.: Cag repeat lengths =335 attenuate the phenotype in the R6/2 Huntington’s disease transgenic mouse. Neurology of Disease. 2009 Mar;33(3):315-330.

Crusio WE, Goldowitz D, Holmes A, Wolfer D.: Standards for the publication of mouse mutant studies. Genes Brain Behav. 2009 Feb;8(1):1-4.

Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, Petersen JL, Zhang Y, Park S, Duex JE, Goldowitz D, Meisler MH, Weisman LS.: VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse. EMBO J. 2008 Dec 17;27(24):3221-34.

Matthews DB, Morrow AL, O’Buckley T, Flanigan TJ, Berry RB, Cook MN, Mittleman G, Goldowitz D, Tokunaga S, Silvers JM.: Acute mild footshock alters ethanol drinking and plasma corticosterone levels in C57BL/6J male, but not DBA/2J or A/J male mice. Alcohol. 2008 Sept;42(6):469-76.

D'Souza CA, Chopra V, Varhol R, Xie YY, Bohacec S, Zhao Y, Lee LL, Bilenky M, Portales-Casamar E, He A, Wasserman WW, Goldowitz D, Marra MA, Holt RA, Simpson EM, Jones SJ.: Identification of a set of genes showing regionally enriched expression in the mouse brain. BMC Neurosci. 2008 Jul 14;9:66.

Matthews DB, Chesler EJ, Cook MN, Cockroft J, Philip VM, Goldowitz D.: Genetic mapping of vocalization to a series of increasing acute footshock using B6.A consomic and B6.D2 congenic mouse strains. Behav Gent. 2008 Jul;38(4): 417-23.

Mittleman G, Goldowitz D, Heck DH, Blaha CD.: Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia. Synapse. 2008 Jul;62(7):544-50.

Reiner A, Del Mar N, Deng YP, Meade CA, Sun Z, Goldowitz D. R6/2 neurons with intranuclear inclusions survive for prolonged periods in the brains of chimeric mice. J. Comp. Neurol. 505(6):603-29. (2007) PMID 17948889

Liu L, Geisert EE, Frankfurter A, Spano AJ, Jiang CX, Yue J, Dragatsis I, Goldowitz D. A transgenic mouse class-III beta tubulin reporter using yellow fluorescent protein. Genesis 45(9):560-9. (2007) PMID 17868115

Kunho Choi, Research Assistant
Domenico Di Curzio, Graduate Research Assistant
Andrew Fam, Undergraduate Academic Assistant
Brendan François, Work Study Student
Randy Glenn, Software Development Manager
Thomas Ha, Postdoctoral Research Fellow
Andrew Jervis, Research Assistant
Matt Larouche, Postdoctoral Research Fellow
Margaret Lo, Work Study Student
Petra Lolic, Undergraduate Academic Assistant
Anna Poon, MSc Student
Derek Rains, Research Assistant
Anita Sham, Research Coordinator
Fiona Song, Work Study Student
Rachel So, Undergraduate Academic Assistant
Douglas Swanson, Research Associate
Suvina To, Undergraduate Academic Assistant
Richard Vo, Research Assistant
Aaron Williams, Undergraduate Academic Assistant
Joanna Yeung, Graduate Research Assistant