Results Through Rehabilitation & Research
Instructor, Neurology and Neuroscience,
Weill Cornell Medical College
Assistant Professor, Chemistry and Life Science,
United States Military Academy
We are interested in understanding the signaling pathways that control axonal growth with the long-term goal of promoting regeneration in humans.
B.S., Biological Sciences
summa cum laude
University of North Texas, 1989-1993
Johns Hopkins University, 1993-1999
Postdoc, Molecular Neuro-Oncology
Rockefeller University, 1999-2004
Research Associate, Molecular Neuro-Oncology
Rockefeller University, 2004-2009
O’Donovan KJ. Combinatorial resistance: the best defense is a good offense. Front. Oncol. 2013; 3:280. doi: 10.3389/fonc.2013.00280.
Reeber SL, O'Donovan KJ. Tracking cell lineage and fate into cerebellar circuits. Cerebellum. 2012; 11(4):829-33.
O’Donovan KJ, Ma KJ, Guo HC, Mercer K, Pritchard CA, Snider WD, Ratan RR, Zhong J. B-RAF kinase mediates TrkA-induced sensory axon growth. Submitted.
O’Donovan KJ, Diedler J, Couture GC, Fak JJ, Darnell RB. The onconeural antigen cdr2 is a novel APC/C target that acts in mitosis to regulate c-myc target genes in mammalian tumor cells. 2010. PLoS ONE 5(4): e10045. PMID: 20383333.
O’Donovan KJ, Darnell RB. Neuronal signaling through alternative splicing: some exons CaRRE. Science STKE. 2001; (94):pe2. PMID: 11752670.
Levkowitz Y, O’Donovan KJ, Baraban JM. Blockade of NGF-induced neurite outgrowth by a dominant-negative inhibitor of the Egr family of transcription regulatory factors. Journal of Neuroscience. 2001; 21(1) 45-52. PMID: 11150318.
O’Donovan KJ, Levkovitz Y, Ahn D, Baraban JM. Functional comparison of Egr3 transcription factor isoforms: Identification of an activation domain in the N-terminal segment absent from Egr3b, a major isoform expressed in brain. Journal of Neurochemistry. 2000; 75, 1352-1357. PMID: 10987814.
O’Donovan KJ, Baraban, JM. Major Egr3 isoforms are generated via alternate translation start sites and differ in their abilities to activate transcription. Molecular and Cellular Biology. 1999; 19: 4711-4718. PMID: 10373520.
Zaman K, Ryu H, Hall D, O’Donovan KJ, Lin KI, Miller MP, Marquis JC, Baraban JM, Semenza GL, Ratan RR. Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21waf1/cip1 and erythropoietin. Journal of Neuroscience. 1999; 19 (22):9821-9830. PMID: 10559391.
O’Donovan KJ, Tourtellotte WG, Milbrandt J, Baraban JM. The Egr family of transcription regulatory factors: progress at the interface of molecular and systems neuroscience. Trends in Neuroscience. 1999; 22,167-173. PMID: 10203854.
O’Donovan KJ, Wilken EP, Baraban JM. Sequential expression of Egr-1 and Egr-3 in hippocampal granule cells following electroconvulsive stimulation. Journal of Neurochemistry. 1998; 70, 1241-1248. PMID: 9489747.
B-RAF drives developmental and regenerative axon growth
We use the dorsal root ganglia (DRG) to investigate long-distance axonal growth. While the RAF-MEK-ERK, PI3K-AKT-mTOR and other pathways have been shown to be required for developmental DRG axon growth, we wanted to know what was sufficient to drive DRG axon growth in vivo. To do so, we used a Cre-inducible constitutively active or kinase-active B-RAF (kaB-RAF) transgene to drive the RAF-MEK-ERK pathway in embryonic DRGs in vivo. These experiments showed that in the absence of upstream neurotrophin signaling, kaB-RAF is sufficient to drive robust developmental axon growth of DRG neurons. Strikingly, kaB-RAF also caused a marked overgrowth of sensory axons in the spinal cord. These data, coupled with the observation that kaB-RAF also promoted robust axon growth of adult DRG neurons in vitro, led us to test whether kaB-RAF could promote the growth of injured axons, which often fail to regenerate.
To formally test whether kaB-RAF can promote regeneration in vivo in adult CNS, we are collaborating with Zhigang He at Harvard, to test whether kaB-RAF-can promote regenerative axon growth in an optic nerve injury model. We are also testing whether kaB-RAF can promote regeneration in a dorsal nerve root injury model developed by the Son lab at Temple University.
Mouse models of cardio-facio-cutaneous syndrome
The other focus of our research, which was funded by a Goldsmith Fellowship, has been the establishment of mouse models of cardio-facio-cutaneous (CFC) syndrome, one of several RASopathies. CFC syndrome is a devastating multi-system disease most often caused by germline mutations in Braf. CFC-affected children display many neurological symptoms including cognitive delay, seizures and motor system defects like ataxia and hypotonia as well as cardiac abnormalities. We have generated two novel CFC mouse models that mimic neurological aspects of the human syndrome, identified biomarkers that tightly correlate with disease onset and are using these mice to test therapeutic strategies to ameliorate disease phenotypes.
Most of the Braf mutations that cause CFC are gain-of-function mutations. To generate different lines of mice, we expressed kaB-RAF in different neuronal subtypes using selective Cre-drivers. One line of mice exhibits ataxia and motor system defects that phenocopy CFC patient neurological symptoms; and molecular defects in the cerebellum, including alterations in Purkinje cell cytoarchitecture and climbing fiber innervation. Importantly, both the behavioral and molecular kaB-RAF-induced defects in these mice can be ameliorated by genetic or pharmacological blockade of downstream MAP kinase effectors as well as by a novel neuroprotective agent. In a second model, we generated mice that exhibit profound macrocephaly, a highly penetrant feature of human CFC. As is often the case for CFC-affected children, the underlying cause of the macrocephaly in these mice is hydrocephalus. These mice provide a platform to test the efficacy of potential pharmacologic treatments for CFC.
Intergovernmental Personnel Act - Telemedicine & Advanced Research Center
Goldsmith Fellowship - Burke and Cornell, 2011-2013