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Intrinsic neuronal determinants of neurite regrowth Borisoff, Jaimie F.

Abstract

Traumatic injury to the central nervous system (CNS) results in neurological deficits, in part, due to axonal regeneration failure. This is functionally exemplified in spinal cord injury by motor and sensory paralysis. Regeneration failure has been attributed to several factors, including intrinsic neuronal limitations to regeneration, as well as numerous inhibitory molecules present in the injured CNS environment. The impact of intrinsic neuronal factors is investigated here. A transition from a permissive to a restrictive repair period exists in the developing chick on approximately embryonic day (E) 13, possibly due to the formation of an extrinsic inhibitory environment preventing axonal growth, and/or an intrinsic inability of mature neurons to regenerate. By fluorescent labeling of brainstem-spinal neurons in ovo, I was able to subsequently track the capacity of specific populations of young (E8) versus mature (El 7) brainstem-spinal neurons to regrow neurites (i.e. presumptive axons) in vitro on permissive growth substrates. When cultured on E8, robust neurite growth was observed from all brainstem populations examined. In contrast, when cultured on El7, significant neurite growth was seen only from raphe-spinal neurons. Thus, brainstem-spinal neurite regrowth may dependent on both neuronal age and phenotype, suggesting that intrinsic neuronal properties may contribute to axonal regeneration failure. Because regeneration may depend on intrinsic neuronal properties, it may be beneficial to pharmacologically enhance the axonal growth capacity of neurons. Injured neurons respond characteristically (i.e. growth cone collapse or neurite retraction) to various molecules that inhibit axonal growth, including myelin proteins and chondroitin sulfate proteoglycans (CSPG). Accordingly, it is possible that intracellular signaling from several inhibitory molecules converge onto a common regulatory pathway of axonal growth inhibition, i.e. the Rho-GTPase. I tested in vitro whether pharmacological inhibition of a major downstream effector of Rho, Rho-kinase (ROCK), promoted neurite outgrowth of dorsal root ganglia (DRG) neurons grown on inhibitory substrates of aggrecan (a CSPG), myelin, and spinal cord cryosections. Indeed, ROCK inhibition promoted neurite outgrowth several-fold, as well as significantly altering the actin-based morphology of growth cones. The data support the notion that suppression of Rho-pathway activity may be a viable therapeutic avenue for enhancing axonal regeneration within the injured adult CNS.

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