Anthony Wynshaw-Boris, MD, PhD

Department of Genetics and Genome Sciences
School of Medicine
James H. Jewell MD ’34 Professor of Genetics
Department of Genetics and Genome Sciences
School of Medicine
Department of Neurosciences
School of Medicine
Department of Pediatrics
School of Medicine
Cancer Genomics and Epigenomics Program
Case Comprehensive Cancer Center

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 Information

Research Projects

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.

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.

External Appointments

Division Chief, Genetics
University Hospitals Rainbow Babies and Children's Hospital
Chairman, Department of Genetics
University Hospitals Cleveland Medical Center