Primary sensory neurons are pseudobipolar neurons with a peripheral axon that regenerates when injured and a centrally projecting axon that does not regenerate following injury. Although neuronal intrinsic factors that positively regulate neurite growth have been well investigated, the negatively intrinsic factors inhibiting neurite growth and corresponding molecular mechanisms need further investigation. Recently researchers from Chinese Academy of Sciences discovered that inhibitor 5 of protein phosphatase 1 (IPP5), a newly identified inhibitory subunit of protein phosphatase 1 (PP1), inhibits neurite growth in primary sensory neurons as an intrinsic regulator.
HAN Qingjian and his colleagues, under the supervision of Dr. BAO Lan from Shanghai Institute of Biochemistry and Cell Biology, CAS, used a series of experiments to show that IPP5 was highly expressed in rat primary sensory neurons localized in the dorsal root ganglion (DRG) and was downregulated after sciatic nerve axotomy. Knocking down IPP5 with specific shRNA increased the length of the longest neurite, the total neurite length and the number of neurite ends in cultured rat DRG neurons. Mutation of the PP1 binding motif “8KIQF12” or the PP1 inhibiting motif at Thr34 eliminated the IPP5-induced inhibition of neurite growth.
Furthermore, biochemical experiments showed that IPP5 interacted with type I transforming growth factor-β receptor (TβRI) and PP1 and enhanced transforming growth factor-β (TGF-β)/Smad signaling in a PP1-dependent manner. Overexpressing IPP5 in DRG neurons aggravated TGF-β-induced inhibition of neurite growth, which was abolished by blocking PP1 or IPP5 binding to PP1. Blockage of TGF-β signaling with TβRI inhibitor SB431542 or Smad2 shRNA attenuated the IPP5-induced inhibition of neurite growth. Thus, these data indicate that selectively expressed IPP5 inhibits neurite growth by maintaining TGF-β signaling in primary sensory neurons.
This work entitled “IPP5 inhibits neurite growth in primary sensory neurons by maintaining TGF-β/Smad signaling” was published in Journal of Cell Science.
This study was supported by grants from Chinese Academy of Sciences, National Natural Science Foundation of China and Ministry of Science and Technology.
A model for IPP5 regulating the TGF-β/Smad signaling pathway and inhibiting neurite growth of primary sensory neurons. After dimerized TGF-βs binding to TβRII, the TβRII recruits and activates TβRI by phosphorylating its GS-domain. PP1 could be targeted to the activated TβRI, and inactivate TβRI by dephosphorylating its GS-domain. IPP5 binds to PP1 and blocks PP1 activity, hence maintains the TGF-β/Smad signaling.
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