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Anthony Wynshaw-Boris
Professor and Chairman
Department of Genetics
School of Medicine
Case Western Reserve University
Biomedical Research Building 731
2109 Adelbert Road
Cleveland, Ohio 44106-4955
Tel: (216) 368-0581
Fax: (216) 368-3432
E-mail: anthony.wynshaw-boris@case.edu


About Anthony Wynshaw-Boris

Tony Wynshaw-Boris received his MD/PhD degrees from Case Western Reserve University School of Medicine. His PhD was under the direction of Richard Hanson, PhD, where he elucidated the sequences within the PEPCK promoter required for activation by cAMP and glucocorticoids. He did his residency in Pediatrics at Rainbow Babies and Children's Hospital, followed by a medical genetics fellowship at Boston Children's Hospital. While in Boston, he did a postdoctoral fellowship at Harvard Medical School under the direction of Philip Leder, MD, where he studied mouse models of developmental disorders. In 1994, Dr. Wynshaw-Boris set up an independent laboratory at the National Human Genome Research Institute of the NIH, where he initiated a program using mouse models to study human genetic diseases, with a focus on neurogenetic diseases. In 1999, he moved to UCSD School of Medicine, where he became Professor of Pediatrics and Medicine, as well as Chief of the Division of Medical Genetics in the Department of Pediatrics. In 2007, he moved to UCSF School of Medicine, where he was the Charles J. Epstein Professor of Human Genetics and Pediatrics, and the Chief of the Division of Medical Genetics in the Department of Pediatrics. In June 2013, he returned to Cleveland to become the Chair of the Department of Genetics and Genome Sciences.


Research

Research in Dr. Wynshaw-Boris's laboratory is focused on understanding genetic and biochemical pathways important for the development and function of the mammalian central nervous system, primarily using mouse models and more recently induced pluripotent stem cells (iPSCs) of human and mammalian diseases to define pathways disrupted in these diseases. There are currently four main projects in the laboratory: the role of the three mouse Dishevelled genes during early development; the genetics and pathophysiology of autism and social behavior, with particular emphasis on pathways responsible for brain overgrowth; human iPSC models of microcephaly and early neurodegeneration caused by mutations in DNA repair and checkpoint genes; and finally the development of a novel concept called Chromosome Therapy, based on the correction of large chromosome aberrations by ring chromosome induction in patient-derived iPSCs. Dr. Wynshaw-Boris has been the Executive Editor of the journal Human Molecular Genetics since 2005. Finally, Dr. Wynshaw-Boris, with his co-editors Charles Epstein and Robert Erickson, published the second edition of their comprehensive book Inborn Errors of Development (2008, Oxford University Press). A third edition is in press.

Dishevelled Mouse Mutants: Examination of a Multifunctional, Redundant Gene Family

Dr. Wynshaw-Boris's laboratory has made mice with mutations in each of the three Dishevelled (Dvl) genes, and they have uncovered partially unique but predominantly redundant functions among the three Dvl genes. In support of unique functions for each of the Dvls, single mutants for Dvl1 display novel social behavior abnormalities, while both Dvl2 and Dvl3 mutants die at birth conotruncal heart defects and display cochlear abnormalities. Dvl1;Dvl3 double mutants display more severe behavioral defects (unpublished) while Dvl1;Dvl2 and Dvl2;Dvl3 double mutants display severe neural tube defects (craniorachischisis) and severe cochlear defects. Finally, Dvl1;Dvl2;Dvl3 triple mutants die soon after implantation, supporting redundant functions among the Dvl genes. They are now using these tools to provide a comprehensive analysis of the role of the canonical Wnt and non-canonical Wnt/PCP pathways during early development. In addition, they are investigating the role of Dvls in complex mammalian behaviors such as social behavior, fear responses and sensorimotor gating.

Autism and Early Brain Overgrowth

A recent interest in the Wynshaw-Boris laboratory is autism. Over the last several years, it is apparent that autism, a highly heritable disorder, appears to be associated with brain overgrowth, although the precise timing and cause of this overgrowth is unknown. They are examining variations in genes and pathways important for neurogenesis, mitosis, and apoptosis in autism. These pathways directly tie in with their studies of Dishevelled pathways and pathways important neuronal migration. Of note, they have found a novel cortical abnormality in postmortem studies of young autistic individuals that may be fundamental to the development of autism. A recent publication found unique abnormalities in gene expression from dorsolateral prefrontal cortex of young autistic patients relative to typically developing children. Currently, they have made iPS cells from autism patients who displayed early brain overgrowth and control, non-autistic individuals with normal brain size to see if there are cellular phenotypes associated with early brain overgrowth.

Human iPSC Models Microcephaly and Neurodegeneration from mutations in DNA Repair and Checkpoint Genes

Microcephaly is commonly found isolated or in more complex syndromic forms of neurodevelopmental diseases, and may be associated with neurological defects, brain structural abnormalities, severe intellectual disabilities and seizures. Mutations in DNA repair genes can lead to microcephaly, demonstrating that maintenance of genomic stability is crucial for proper neurodevelopment and head size. It is likely that microcephaly caused by mutations in DNA repair genes involves abnormal proliferation and/or increased apoptosis during neurogenesis, but mechanisms responsible for microcephaly are poorly understood. We have generated induced Pluripotent Stem Cell (iPSC) models from patients with microcephaly caused by mutations in the DNA repair pathways genes LIG4, PNKP and NBN. As controls, we have made isogenic patient lines that correct the mutations in these genes by CRISPR/Cas9 genome editing, iPSCs from patients with mutations in the ATM gene, which is important for response to DNA damage but does not display microcephaly, and iPSCs from non affected individuals. We used these patient-derived and control iPSCs to generate neuronal precursor cells (NPCs) and cortical neurons, as well as three dimensional cerebral organoids. These tools will allow us to study proliferation, apoptosis and differentiation of uniform populations of cells as well as early self-arranged neuronal structures in the organoids.

Chromosome Therapy: Correction of large chromosome aberrations by ring chromosome induction in patient-derived iPSCs

Approximately 1 in 500 newborn infants are born with chromosomal abnormalities that include trisomies, translocations, large deletions and duplications. There is currently no therapeutic approach for correcting such chromosomal aberrations in vivo or in vitro. Recently, we attempted to produce induced pluripotent stem cell (iPSC) models from patients that contained ring chromosomes: one with a ring chromosome 17 (r17) and two patients with different ring chromosome 13s (r13). Surprisingly, while all three of lines were reprogrammed to iPSCs efficiently, the ring chromosomes were eliminated and replaced by a duplicated normal copy of chromosome 17 in the r17 line and normal copies of chromosome 13 in the r13 lines (Bershteyn et al. 2014, Nature 506:99). This finding suggested a potential therapeutic strategy to correct large-scale chromosomal aberrations. We hypothesized that a chromosome with a large aberration could be corrected by producing a ring chromosome from the aberrant chromosome in iPSCs, which would then be eliminated and replaced by a normal chromosome. We are testing this hypothesis by attempting to induce ring formation in patients with large deletions of chromosome 17 via a Cre/loxP approach. If successful, we will have a generalizable system of "chromosome therapy" for the correction of large chromosomal aberrations by the induction of ring chromosomes through genome editing followed by loss of the ring and duplication of the normal chromosome.


Selected Publications

Bershteyn M, Hayashi Y, Desachy G, Hsiao EC, Sami S, Tsang KM, Weiss LA, Kriegstein AR, Yamanaka S, Wynshaw-Boris A (2014)
Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells.
Nature;:
See PubMed abstract

Moon HM, Youn YH, Pemble H, Yingling J, Wittmann T, Wynshaw-Boris A (2013)
LIS1 controls mitosis and mitotic spindle organization via the LIS1-NDEL1-dynein complex.
Hum Mol Genet;:
See PubMed abstract

Cheah PS, Ramshaw HS, Thomas PQ, Toyo-Oka K, Xu X, Martin S, Coyle P, Guthridge MA, Stomski F, van den Buuse M, Wynshaw-Boris A, Lopez AF, Schwarz QP (2012)
Neurodevelopmental and neuropsychiatric behaviour defects arise from 14-3-3ΞΆ deficiency.
Mol Psychiatry;17(4):451-66
See PubMed abstract

Chow ML, Winn ME, Li HR, April C, Wynshaw-Boris A, Fan JB, Fu XD, Courchesne E, Schork NJ (2012)
Preprocessing and Quality Control Strategies for Illumina DASL Assay-Based Brain Gene Expression Studies with Semi-Degraded Samples.
Front Genet;3:11
See PubMed abstract

Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR, Weiss L, Fan JB, Murray S, April C, Belinson H, Fu XD, Wynshaw-Boris A, Schork NJ, Courchesne E (2012)
Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages.
PLoS Genet;8(3):e1002592
See PubMed abstract

Pramparo T, Libiger O, Jain S, Li H, Youn YH, Hirotsune S, Schork NJ, Wynshaw-Boris A (2011)
Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.
PLoS Genet;7(3):e1001331
See PubMed abstract

Chow ML, Li HR, Winn ME, April C, Barnes CC, Wynshaw-Boris A, Fan JB, Fu XD, Courchesne E, Schork NJ (2011)
Genome-wide expression assay comparison across frozen and fixed postmortem brain tissue samples.
BMC Genomics;12:449
See PubMed abstract

Youn YH, Pramparo T, Hirotsune S, Wynshaw-Boris A (2009)
Distinct dose-dependent cortical neuronal migration and neurite extension defects in Lis1 and Ndel1 mutant mice.
J Neurosci;29(49):15520-30
See PubMed abstract

Yamada M, Yoshida Y, Mori D, Takitoh T, Kengaku M, Umeshima H, Takao K, Miyakawa T, Sato M, Sorimachi H, Wynshaw-Boris A, Hirotsune S (2009)
Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.
Nat Med;15(10):1202-7
See PubMed abstract

Mori D, Yamada M, Mimori-Kiyosue Y, Shirai Y, Suzuki A, Ohno S, Saya H, Wynshaw-Boris A, Hirotsune S (2009)
An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics.
Nat Cell Biol;11(9):1057-68
See PubMed abstract

Yingling J, Youn YH, Darling D, Toyo-Oka K, Pramparo T, Hirotsune S, Wynshaw-Boris A (2008)
Neuroepithelial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division.
Cell;132(3):474-86
See PubMed abstract

Mei X, Wu S, Bassuk AG, Slusarski DC (2007)
Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis.
Dis Model Mech;6(3):679-88
See PubMed abstract

Toyo-oka K, Shionoya A, Gambello MJ, Cardoso C, Leventer R, Ward HL, Ayala R, Tsai LH, Dobyns W, Ledbetter D, Hirotsune S, Wynshaw-Boris A (2003)
14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome.
Nat Genet;34(3):274-85
See PubMed abstract

Gambello MJ, Darling DL, Yingling J, Tanaka T, Gleeson JG, Wynshaw-Boris A (2003)
Multiple dose-dependent effects of Lis1 on cerebral cortical development.
J Neurosci;23(5):1719-29
See PubMed abstract

Sasaki S, Shionoya A, Ishida M, Gambello MJ, Yingling J, Wynshaw-Boris A, Hirotsune S (2000)
A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system.
Neuron;28(3):681-96
See PubMed abstract

Hirotsune S, Fleck MW, Gambello MJ, Bix GJ, Chen A, Clark GD, Ledbetter DH, McBain CJ, Wynshaw-Boris A (1998)
Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality.
Nat Genet;19(4):333-9
See PubMed abstract

Lijam N, Paylor R, McDonald MP, Crawley JN, Deng CX, Herrup K, Stevens KE, Maccaferri G, McBain CJ, Sussman DJ, Wynshaw-Boris A (1997)
Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1.
Cell;90(5):895-905
See PubMed abstract