Assistant Professor, Neurology and Neuroscience
Weill Cornell Medical College
The primary focus of our laboratory is to delineate the molecular mechanisms that drive and direct axon growth, connectivity and regeneration in vivo.
In mammalian embryos, axons grow vigorously and precisely to interconnect the nervous system, and form connections to sensory receptors, to muscles and to internal organs. In the mature nervous system, axon growth stops. After an injury, axons do regenerate (if imperfectly) in the peripheral nervous system, but no productive regeneration occurs in the central nervous system. Because of this lack of axon regeneration, spinal cord injuries, for example, result in permanent paralysis, and retinal axon degeneration in glaucoma causes irreversible loss of vision.
Two reasons have been suggested for why axons cannot re-grow in the mature CNS. First, cell-intrinsic growth pathways are downregulated as the nervous system matures, and second, the mature CNS expresses surface molecules that inhibit axon growth and thereby stabilize the mature configuration. Previous work has clearly shown that injured adult neurons in the CNS can in principle re-grow axons under certain circumstances. However, such axonal regrowth or sprouting have not been able to reach their targets due to limited length and density of regenerative growth.
Our current major focus is to attempt driving axon regeneration in the injured optic nerve, which is a part of the CNS, by genetic activation in mature retinal neurons of pathways that we know can drive axon growth in embryonic neurons. We use several lines of genetically modified mice that allow us to selectively activate or inactivate specific signaling molecules in the nervous system shortly before nerve injury. We then assess regeneration phenotypes using high-resolution imaging, and we test for possible recovery of visual behaviors.
Additional current projects in our lab include the development of novel "transsynaptic tracer mice" that would enables us to visualize the entire network of neurons connected to an initial neuron or a population of neurons of interest, and to modulate gene activity in these neurons. This mouse model will be useful for a number of purposes, for example for the delineation of neuropathic pain circuitry, or to document axon regrowth and rewiring in a regeneration context.
Finally, we have developed several mouse models which mimic the neuronal aspects of human Neuro-Cardio-Facio-Cutaneous Syndromes (NCFCS). We plan to use these mice to devise and test possible therapeutic strategies targeting the very diverse symptoms associated with NCFCS.
In summary, our laboratory uses advanced genetically modified mouse models to dissect the signaling cascades directing axon growth, regeneration and neuronal functionality in vivo.
Dr. Zhong received his Ph.D. (Dr. rer. nat) from the Ruhr University Bochum, Germany, in 1997. He conducted postdoctoral research in the laboratories of Dr. Paul Patterson (Caltech, Pasadena, CA) and Dr. Bill Snider (University of North Carolina, Chapel Hill, NC). Dr. Zhong is an ad hoc reviewer for Nature Neuroscience, Neuron, Journal of Neuroscience, EMBO Reports and European Journal of Neuroscience as well as for the NIH "Neural Differentiation, Plasticity, Regeneration, and Rhythmicity (NDPR)" and "Cellular and Molecular Biology of Glia (CMBG)" study sections.
O’Donovan KJ, Ma K, Guo H, Wang C, Sun F, Han SB, Kim H, Wong J, Charron J, Zou H, Son Y-J, He Z, Zhong J (2014) B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS. J Exp Med (in press).
Zhong J, Zou H (2014) BMP Signaling in Axon Regeneration. Curr Opin Neurobiol (in press).
Zhao Z, Huo F, Jeffry J, Hampton L, Demehri S, Kim S, Liu X, Barry DM, Wan L, Liu Z, Li H, Turkoz A, Ma K, Cornelius LA, Kopan R, Battey JF Jr, Zhong J*, Chen Z* (*co-corresponding authors) (2013) Chronic itch development in sensory neurons requires BRAF signaling pathways. J Clin Invest 123:4769-4780.
Li X, Newbern JM, Wu Y, Morgan-Smith M, Zhong J, Charron J, Snider WD (2012) MEK Is a Key Regulator of Gliogenesis in the Developing Brain. Neuron 75, 1035–1050.
Newbern JM, Li X, Shoemaker SE, Zhou J, Zhong J, Wu Y, Bonder D, Hollenback S, Coppola G, Geschwind DH, Landreth GE, Snider WD (2011) Specific functions for ERK/MAPK signaling during PNS development. Neuron 69:91-105.
Newbern J, Zhong J, Wickramasinghe S, Li X, Wu Y, Samuels I, Cherosky N, Karlo J, O'Loughlin B, Wikenheiser J, Gargesha M, Doughman Y, Charron J, Ginty DD, Watanabe M, Saitta S, Snider WD, Landreth G (2008) Mouse and human phenotypes indicate a critical conserved role for the ERK2 signaling pathway in neural crest development. Proc Natl Acad Sci USA 105:17115-20.
Zhong J, Li X, McNamee C, Chen A, Baccarini M, Snider WD (2007) Raf kinase signaling functions in sensory neuron differentiation and axon growth in vivo. Nat Neurosci 10:598-607.
(Featured as a must-read paper by UCSD's The Signaling Gateway)
Zhong J, Pevny L, Snider WD (2006) "Runx"ing towards sensory differentiation. Neuron 49(3), 325-7.
Zhou FQ, Zhong J, Snider WD (2003) Extracellular crosstalk: when GDNF meets N-CAM. Cell 113:814-5.
Markus A, Zhong J, Snider WD (2002) Raf and Akt mediate distinct aspects of sensory axon growth. Neuron 35:65-76.
Snider WD, Zhou FQ, Zhong J, Markus A (2002) Signaling the pathway to regeneration. Neuron 35:13-6.
Zhong J, Dietzel ID, Kopf M, Wahle P, Heumann R (1999) Sensory Impairments and Delayed Regeneration of Sensory Axons in Interleukin-6-Deficient Mice. J Neurosci 19:4305-4313.
Identification of RAF Downstream Effectors that Drive Axon Growth
We have recently identified the B-RAF kinase signaling as a key player in embryonic axon growth signaling, and are testing B-RAF as a possible driver of regenerative growth. To identify the effectors that mediate B-RAF dependent growth, we mate B-RAF gain-of-function mice with mice carrying effector loss-of-function alleles, and analyze axon growth in the offspring. To complement this approach, we also screen gene expression specifically induced or suppressed by B-RAF in nervous system tissues.
Development of a Novel Transsynatic Tracer Mouse Line
The reliable tracing of axonal connections is essential for any deeper understanding of nervous system function. Many tracing methods are available, but none allow reliable tracing beyond the second synaptic connection in vivo. We have designed a genetic strategy to enable multi-synaptic tracing of axonal connectivity in vivo, starting with any given neuron or neuron population of interest.
Mouse Models for Neuro-Cardio-Facio-Cutaneous Syndromes (NCFCS)
The NCFCS, which include Leopard Syndrome, Noonan Syndrome and Neurofibromatosis type I, are linked to loss- and gain-of function mutations in the RAF signaling pathway. We have observed phenotypes reminiscent of NCFCS in several of our mouse lines that carry RAF-related genetic manipulations. We are investigating and comparing these phenotypes in depth, and devising genetic strategies to counteract the NCFCS-like symptoms in vivo.
National Institutes of Health
1R01EY022409-01, National Eye Institute
PI: Jian Zhong
Title: B-RAF Drives Regenerative Axon Growth in the Optic Nerve in vivo
Dates: 05/2012 — 04/2017
Three year research grant, 2010-08-61
PI: Jian Zhong
Title: RAF Signaling in Sensory-Motor Circuit Formation
Dates: 08/2010 — 07/2013
Christopher & Dana Reeve Foundation
PI: Jian Zhong
Title: Enabling axon regeneration by turning the neurons back to their youth