Research

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.

"We believe that identifying the mechanisms regulating developmental events is requisite for understanding the basis of most biological disorders and is essential both for prevention and the development of strategies to repair damage to the nervous system due to genetic defects, tumors, or injuries to the brain or spinal cord."

The cerebral cortex, the outermost layer of neurons commonly referred to as gray matter, is the largest and most complex component of the brain. Although initially all stem cells in charge of building it are created equal, they quickly commit irrevocably to forming specific cortical regions. How the stem cells' destiny is determined, however, has remained an open question.

During embryonic brain development, the stem cells that will give rise to the cerebral cortex pass through a series of tightly regulated stages. Early during neurogenesis, stem cell-like progenitor cells known as neuroepithelial cells undergo cell division to expand their own pool. Later, they differentiate into more mature progenitor cells called radial glia, which produce a constant stream of both progenitors and neurons, the latter migrating outward to establish the gray matter of specialized cortical regions. The defining characteristic of the progenitor cells that will go on to form the cerebral cortex is their expression of a transcription factor called Emx1.

After discovering that a specific member of the fibroblast growth factor family of morphogens controls the timing of the critical transition period bridging the early expansion phase of neuroepithelial cells and the later neurogenic phase of radial glia, O'Leary hypothesized that the regional identity of progenitors in the Emx1 lineage may involve one or more transcription factors that define unique subpopulations of progenitors via differences in their expression levels. A promising candidate was the LIM transcription factor Lhx2, which is expressed in all progenitors of the Emx1 lineage but at different levels in a graded regional pattern. By creating a new genetically engineered mouse line, his team deleted Lhx2 from neuroepithelial cells at different times during embryonic development and demonstrated that Lhx2 regulated their destiny.

These findings may help expand understanding of the genetic underpinnings of many neurodegenerative disorders, as well as eventually provide the means to direct stem cells to repair specific parts of the brain ravaged by disease or injury.

Left to right:
Front row: Yoo-Shick Lim, Andreas Zembrzycki, Dennis O'Leary, Rosalind Carney, Haydee Gutierrez

Back row: Adam Stocker, Zoila Babotriera, Scott May, Carlos Perez-Garcia, Berta Higgins, Setsuko Sahara, Suzanna Chan, Todd McLaughlin, Shen-Ju Chou

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]

Salk News Releases

• Salk to accelerate brain research with $4.5 million NIH grant
  October 12, 2011
• Genetics of Patterning the Cerebral Cortex: How stem cells yield functional regions in "gray matter"
  October 12, 2009
• Timing is everything: Growth factor keeps brain development on track
  July 17, 2009
• Salk scientist receives 2007 Krieg Cortical Discoverer Prize
  October 16, 2007
• Researchers uncover novel mechanism that balances the sizes of functional areas in the brain
  September 12, 2007
• A second career for a growth factor receptor: keeping nerve axons on target
  September 11, 2008
• When it comes to "talent," size of brain components does matter – but bigger isn't necessarily better
  March 7, 2007
• Salk and Stanford teams join forces to reveal two paths of neurodegeneration
  June 15, 2006
• Neurons find their place in the developing nervous system with the help of a sticky molecule
  May 2, 2006
• Molecular 'zipcode' guides nerves to correct places in body
  April 7, 2005
• Binocular Vision Discovery Provides Insights for Stem Cell Therapy
  November 12, 2004
• Waves of Nerve Cell Activity Create Sharp Vision in the Brain
  December 18, 2003
• New Insight Into How Eyes Become Wired To The Brain Discovered By Salk, UT Southwestern Scientists
  September 1, 2002
• First Genes To Control Cortex Identity Discovered By Salk Scientists
  April 13, 2000

Awards and Honors

• 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

Links

O'Leary lab

O'Leary technologies available for licensing