Abstract
Mature retinal ganglion cells (RGCs) do not normally regenerate severed axons after optic nerve injury and show only little neurite outgrowth in culture. However, RGCs can be transformed into an active regenerative state after lens injury (LI) enabling these neurons to regrow axons in vitro and in vivo. In the current study we investigated the role of CK1δ and CK1ε activity in neurite outgrowth of LI stimulated RGCs and nerve growth factor (NGF) stimulated PC12 cells, respectively. In both cell types CK1δ and ε were localized in granular particles aligned at microtubules in neurites and growth cones. Although LI treatment did not measurably affect the expression of CK1δ and ε, it significantly elevated the specific kinase activity in the retina. Similarly, CK1δ/ε specific kinase activity was also elevated in NGF treated PC12 cells compared with untreated controls. Neurite extension in PC12 cells was associated with a change in the activity of CK1δ C-terminal targeting kinases, suggesting that activity of these kinases might be necessary for neurite outgrowth. Pharmacological inactivation of CK1δ and ε markedly compromised neurite outgrowth of both, PC12 cells and LI stimulated RGCs in a concentration dependent manner. These data provide evidence for a so far unknown, but essential role of CK1 isoforms in neurite growth.
Highlights
Neurons of the central nervous system (CNS) are normally unable to regenerate injured axons
In previous reports we have shown a low to moderate expression of CK1d and CK1e in the inner nuclear layer (INL) of rat retina and a significantly stronger staining in bIII-tubulinpositive retinal ganglion cells (RGCs) [44,45]
In order to test whether CK1d and e expression is altered in injured RGCs or when these neurons enter into a regenerative state adult rats were subjected either to an optic nerve cut (ONC) or ONC+lens injury (LI)
Summary
Neurons of the central nervous system (CNS) are normally unable to regenerate injured axons. The molecular processes and regulatory proteins involved in the rearrangement of the cytoskeleton and the regulation of neurite growth in mature RGCs are still poorly understood. Several kinases such as p38 MAPK, ROCK, PKC and PI3K have been identified to regulate axon growth cone stability and guidance [17,18,19,20,21,22]. Studies using RNA interference based screening suggested that approximately 8–9% of the human kinome are involved in promoting or inhibiting neurite outgrowth [23]
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