Abstract
Axon regeneration in the central nervous system is inefficient. However, the neurons in the peripheral nervous system display robust regeneration after injury, indicating that axonal regeneration is differentially controlled under various conditions. To identify those molecules regulating axon regeneration, comparative analysis from dorsal root ganglion neurons at embryonic or adult stages is utilized, which reveals that PDK1 is functions as a negative regulator of axon regeneration. PDK1 is downregulated in embryonic neurons after axotomy. In contrast, sciatic nerve axotomy upregulated PDK1 at protein levels from adult mice. The knockdown of PDK1 or the chemical inhibition of PDK1 promotes axon regeneration in vitro and in vivo. Here we present PDK1 as a new player to negatively regulate axon regeneration and as a potential target in the development of therapeutic applications.
Highlights
Most neurons fail to regenerate axons in the central nervous system (CNS), some neurons in the peripheral nervous system (PNS) successfully regenerate their injured axons to fully recover their original function [1]
Axotomy induced the downregulation of axonal PDK1 in embryonic Dorsal root ganglion (DRG) neurons in vitro To understand the role of PDK1 in axon regeneration, we utilized in vitro sensory neuron cultures prepared from embryonic mouse dorsal root ganglions (DRGs) because of their high regenerative capacity [11] and found that axotomy induced downregulation of PDK1 at the protein level (Fig. 1a)
Analysis of the total protein lysates prepared from mouse embryonic DRG neurons revealed that axotomy reduced PDK1 protein levels without significantly changing the mRNA levels (Fig. 1b and c), suggesting that PDK1 downregulation is regulated at the protein level after injury
Summary
Most neurons fail to regenerate axons in the central nervous system (CNS), some neurons in the peripheral nervous system (PNS) successfully regenerate their injured axons to fully recover their original function [1]. The robust axon regeneration in the PNS is orchestrated by multiple kinases responsible for regulating injury responses [2,3,4,5,6]. Identifying the kinases that regulate regeneration offers the opportunity to manipulate the intrinsic regenerative potential by directly modulating kinase activity and related pathways. Phosphoinositide 3-dependent kinases are involved in regulating many biological processes [7]. 3-phosphoinositide-dependent protein kinase-1 (PDK1), regulated by growth factors and hormones, is a pivotal member of this signaling pathway. PDK1 has been found to play an essential role in cell survival, differentiation, and proliferation via the phosphorylation and activation of the AGC protein kinase family, including protein
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