Salk Institute
Dennis D. M. O'Leary
Molecular Neurobiology Laboratory
Vincent J. Coates Chair in Molecular Neurobiology
Dennis D. M. O'Leary

Molecular Neurobiology Laboratory
Vincent J. Coates Chair in Molecular Neurobiology


Dr. Dennis O'Leary, a Professor in the Molecular Neurobiology Laboratory, studies development and plasticity of the vertebrate nervous system. Among the issues that Dr. O'Leary's research team focuses on are: (1) forebrain development and patterning, especially the specification and differentiation of the functionally specialized areas of the cortex and related parts of the brain and spinal cord, and (2) axon guidance and development of neural maps, particularly between the eye and the brain. His group also have strong interests in stem cell biology and the effects of developmental plasticity on behavioral performance. Among their findings is the first demonstration of the genetic control of area patterning of the neocortex and the genes that specify the identities of the primary areas that process sensory information and control motor output. In addition, Dr. O'Leary's group has defined roles for the first guidance molecules that control the development of neural mapping, the Ephs and ephrins. Their work has made novel relationships between neural plasticity and behavioral performance. Dr. O'Leary's goal is to understand fundamental developmental events, and to use this knowledge to make the most efficient theraputic use of stem cell biology and to design effective strategies to overcome birth defects, neurological diseases and disorders, and neural injury.

"Identifying mechanisms that regulate brain development is requisite for understanding the basis of most neurological disorders and disease and is essential both for prevention and for developing repair strategies."

Dennis O'Leary, together with his research group, studies critical genetic and molecular mechanisms that regulate brain development, using the mouse as a primary model system. His work focuses on two important questions: how the brain assembles itself during development, including its wiring, and how different parts of the cerebral cortex, the largest and most complex part of the brain, become uniquely specialized to perceive vision and touch, as well as generate movements. O'Leary's goal is to understand the mechanisms used by the brain to accomplish these crucial tasks, providing the knowledge required to prevent genetic disorders and disease or to repair defects.

O'Leary's previous work demonstrated that specific wiring between parts of the brain or from the eye to the brain arises from initially exuberant connections between neurons, followed by a selective pruning, occurring by the degeneration of many of the early connections to retain only the correct ones. These connections are formed by axons, the outgoing "wires" on each cell that convey electrochemical impulses between neurons. Among O'Leary's current work, he is studying the molecular mechanisms that decide which axons die or live, and once this selection is made, how those axons fated for death are actually eliminated. This work has important implications for the mechanisms that underlie most, if not all, neurodegenerative diseases, including Alzheimer's and Parkinson's.

In a distinct set of projects, O'Leary has recently identified specific transcription factors (proteins that regulate large sets of genes to specify the properties of cells and tissues) that specify progenitors, or natural stem cells, in the developing brain to make parts of the cerebral cortex that are specialized to process vision or touch. By manipulating these genes in mice, he can, for example, make the visual or touch processing parts of the cerebral cortex larger or smaller, which initiates a cascade of changes in other parts of the brain outside the cerebral cortex and has a significant influence on behavior. This work has implications for many neurological disorders, including autism and other genetic- based brain disorders that have prominent behavioral components.

A common link among the studies performed by O'Leary and his research team is the identification of genes that control important developmental functions and the molecular mechanisms by which they operate, thereby providing a framework for potential treatments in the future.

Lab Photo

Left to right:
Kyucheol Cho, Yoo-Shick Lim, Daichi Kawaguchi, Adam Stocker, Carlos G. Perez- Garcia, Dennis O'Leary, Todd McLaughlin, Andreas Zembrzycki, Berta Higgins, Haydee Gutierrez, Brenda Beckett

Selected Publications

Leingartner A, Thuret S, Kroll TT, Chou S-J, Leasure JL, Gage FH & O'Leary DDM 2007 Sizes of somatosensory and motor cortical areas determine proficiency at tactile and motor behaviors. Proc. Natl. Acad. Sci. USA, 104:4153-4158.

Hoopfer ED1, McLaughlin T1, Watts RJ, Schuldiner O & O'Leary DDM2, Luo L2 2006

Wlds protection distinguishes axon degeneration following injury from naturally-occurring developmental pruning. Neuron 50:883-895. [1, co-first authors; 2, co-communicating authors]

Takeuchi A & O'Leary DDM 2006 Radial migration of superficial layer cortical neurons controlled by novel Ig cell adhesion molecule, MDGA1. Journal of Neuroscience 26:4460-4464.

Pak W, Hindges R, Lim Y-S, Pfaff SL & O'Leary DDM 2004. Magnitude of binocular vision controlled by Islet-2 repression of a genetic program that specifies laterality of retinal axon pathfinding. Cell 119:567-578.

Hamasaki T*, Leingartner A*, Ringstedt T & O'Leary DDM 2004. EMX2 regulates sizes and positioning of the primary sensory and motor areas in neocortex by direct specification of cortical progenitors. Neuron 43:359-372

McLaughlin, T1, Torborg, CL1, Feller, MB2, O'Leary, DDM2 (2003) Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development. Neuron 40:1147-1160. [1co-first authors; 2co-corresponding authors]

McLaughlin, T, Hindges, R, Yates, PA, O'Leary, DDM (2003) Bifunctional action of ephrin-B1 as a repellent and attractant to control bidirectional branch extension in dorsal-ventral retinotopic mapping. Development 130:2407-2418.

Hindges, R1, McLaughlin, T1, Genoud, N, Henkemeyer, M, O'Leary, DDM (2002) EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping. Neuron 35:475-487. [1co-first authors]

Erkman, L, Yates, PA, McLaughlin, T, ... O'Leary, DDM1, Rosenfeld, MG1 (2000) A POU domain transcription factor dependent program regulates axon pathfinding in the vertebrate visual system. Neuron 28:779-792. [1co-corresponding authors]

Bishop, KM, Goudreau, G, O'Leary, DDM (2000) Emx2 and Pax6 regulate area identity in the mammalian neocortex. Science 288:344-349.

Brown, A1, Yates, PA1, Burrola, P, Ortuño, D, Vaidya, A, Jessell, TM, Pfaff, SL, O'Leary, DDM, Lemke, G (2000) Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell : 102:77-88. [1co-first authors]

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Awards and Honors

  • American Academy of Arts and Sciences 2015
  • Javits Investigator Award, National Institute of Neurological Disorders and Stroke,
    National Institutes of Health 2004
  • AAAS Fellow, American Association for the Advancement of Science 2003
  • Ariens-Kappers Award Laureate, Royal Netherlands Academy of Arts and Sciences 2003
  • ISI Highly Cited Researcher 2002
  • Senior Editor, Journal of Neuroscience 1993 - 2002
  • McKnight Investigator Award 1999
  • Capputto Memorial Award from Argentina Society for Neuroscience 1999
  • Decade of the Brain Medalist, American Association Neurological Surgeons 1996
  • Young Investigator Award, Society for Neuroscience 1991
  • Krieg Cortical Explorer Award 1988
  • McKnight Scholars Award 1987
  • Alfred P. Sloan Research Fellow 1987

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