Optic nerve damage and regeneration failure are major features of glaucoma, inherited and traumatic optic neuropathies, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. By using an intraorbital optic nerve injury model in adult mice, we discovered that conditional deletion of SOCS3 and PTEN/TSC1 in RGCs promotes significant neuronal survival and axon regeneration. Our further studies suggested mTOR as a critical mediator of axon regeneration after PTEN/TSC1 deletion, likely by controlling the ability of injured neurons to synthesize materials for axon growth. On the other side, our data suggested that axon regeneration after SOCS3 deletion depends on gp130 signaling. In this proposal, we will address the following questions: First, what is the effector of SOCS deletion in promoting neuronal survival and axon regeneration and whether SOCS3 is the only key negative regulator? Second, do SOCS3-dependent and PTEN/TSC1-dependent pathways interact? Third, are regenerating axons able to find their pathway and mediate functional recovery? We expect that these experiments will provide important insights into the understanding the mechanisms of optic axon regeneration and the development of neural repair therapeutics.
Optic nerve damage and regeneration failure are major features of glaucoma, inherited and traumatic optic neuropathies, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. By AAV-Cre-assisted conditional knockout of floxed mouse genes, we recently made an exciting discovery that deletion of SOCS3 (suppressor of cytokine signaling 3) in adult retinal ganglion cells (RGCs) enables robust long-distance axon regeneration after intraorbital optic nerve injuries, revealing a potentially important signaling pathway in regulating axon regenerative ability of mature CNS neurons. The objectives of this proposed study are two-folds: to determine the underlying mechanisms permitting axon regeneration in SOCS3-deleted neurons and to assess whether the regenerating axons could find the normal projection pathway and re-form synaptic connections with their central targets.
|Cartoni, Romain; Norsworthy, Michael W; Bei, Fengfeng et al. (2016) The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration. Neuron 92:1294-1307|
|Duan, Xin; Qiao, Mu; Bei, Fengfeng et al. (2015) Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 85:1244-56|
|Belin, Stephane; Nawabi, Homaira; Wang, Chen et al. (2015) Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics. Neuron 86:1000-14|
|Belin, Stephane; Norsworthy, Michael; He, Zhigang (2014) Independent control of aging and axon regeneration. Cell Metab 19:354-6|
|O'Donovan, Kevin J; Ma, Kaijie; Guo, Hengchang et al. (2014) B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS. J Exp Med 211:801-14|
|Lu, Yi; Belin, StÃ©phane; He, Zhigang (2014) Signaling regulations of neuronal regenerative ability. Curr Opin Neurobiol 27:135-42|
|Nawabi, Homaira; Zukor, Katherine; He, Zhigang (2012) No simpler than mammals: axon and dendrite regeneration in Drosophila. Genes Dev 26:1509-14|
|Hu, Yang; Park, Kevin K; Yang, Liu et al. (2012) Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron 73:445-52|
|Sun, Fang; Park, Kevin K; Belin, Stephane et al. (2011) Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480:372-5|