PTPσ Knockdown in Lampreys Impairs Reticulospinal Axon Regeneration and Neuronal Survival After Spinal Cord Injury

Rodemer, William; Zhang, Guixin; Sinitsa, Isabelle; Hu, Jianli; Jin, Li-Qing; Li, Shuxin; Selzer, Michael E.

doi:10.3389/fncel.2020.00061

Cited by 7 publications

(9 citation statements)

References 66 publications

(94 reference statements)

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“…Our group used antisense morpholinos (MOs) to knock down lamprey PTPσ in vivo and studied its direct effects on the axon regeneration and retrograde neuronal death after SCI. Unexpectedly, we found that PTPσ knockdown in lamprey reduced axon regeneration and neuronal survival beginning between 10 and 20 weeks after TX (Rodemer et al, 2020). Those results seem to be inconsistent with the putative role of PTPσ in mammalian axon regeneration (Lang et al, 2015), and with the correlation between PTPσ mRNA and post-TX retrograde apoptotic signaling seen even after ChABC treatment in current study.…”

Section: Role Of Ptpσ In Axon Regenerationcontrasting

confidence: 89%

“…Those results seem to be inconsistent with the putative role of PTPσ in mammalian axon regeneration ( Lang et al, 2015 ), and with the correlation between PTPσ mRNA and post-TX retrograde apoptotic signaling seen even after ChABC treatment in current study. In our previous report, the lack of activated caspases in RS neurons, and the long latency after PTPσ knockdown in vivo indicated that enhanced supraspinal neuronal death might result from non-apoptotic mechanisms: by incidentally transfected infiltrating immune cells, or trophic deprivation, or autonomous autophagic mechanisms ( Rodemer et al, 2020 ). It also is possible that the redundancy of CSPG receptors mitigated the beneficial effect of in vivo PTPσ knockdown.…”

Section: Discussionmentioning

confidence: 99%

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Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

Rodemer

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Paralysis following spinal cord injury (SCI) is due to failure of axonal regeneration. It is believed that axon growth is inhibited by the presence of several types of inhibitory molecules in central nervous system (CNS), including the chondroitin sulfate proteoglycans (CSPGs). Many studies have shown that digestion of CSPGs with chondroitinase ABC (ChABC) can enhance axon growth and functional recovery after SCI. However, due to the complexity of the mammalian CNS, it is still unclear whether this involves true regeneration or only collateral sprouting by uninjured axons, whether it affects the expression of CSPG receptors such as protein tyrosine phosphatase sigma (PTPσ), and whether it influences retrograde neuronal apoptosis after SCI. In the present study, we assessed the roles of CSPGs in the regeneration of spinal-projecting axons from brainstem neurons, and in the process of retrograde neuronal apoptosis. Using the fluorochrome-labeled inhibitor of caspase activity (FLICA) method, apoptotic signaling was seen primarily in those large, individually identified reticulospinal (RS) neurons that are known to be “bad-regenerators.” Compared to uninjured controls, the number of all RS neurons showing polycaspase activity increased significantly at 2, 4, 8, and 11 weeks post-transection (post-TX). ChABC application to a fresh TX site reduced the number of polycaspase-positive RS neurons at 2 and 11 weeks post-TX, and also reduced the number of active caspase 3-positive RS neurons at 4 weeks post-TX, which confirmed the beneficial role of ChABC treatment in retrograde apoptotic signaling. ChABC treatment also greatly promoted axonal regeneration at 10 weeks post-TX. Correspondingly, PTPσ mRNA expression was reduced in the perikaryon. Previously, PTPσ mRNA expression was shown to correlate with neuronal apoptotic signaling at 2 and 10 weeks post-TX. In the present study, this correlation persisted after ChABC treatment, which suggests that PTPσ may be involved more generally in signaling axotomy-induced retrograde neuronal apoptosis. Moreover, ChABC treatment caused Akt activation (pAkt-308) to be greatly enhanced in brain post-TX, which was further confirmed in individually identified RS neurons. Thus, CSPG digestion not only enhances axon regeneration after SCI, but also inhibits retrograde RS neuronal apoptosis signaling, possibly by reducing PTPσ expression and enhancing Akt activation.

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Section: Role Of Ptpσ In Axon Regenerationcontrasting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

Rodemer

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…In lampreys, both LAR and PTPσ are expressed selectively in neurons that regenerate poorly post-axotomy (Zhang et al, 2014 ). Paradoxically, knockdown of PTPσ by retrograde delivery of morpholinos from the transection site was followed by inhibition of regeneration and reduction in some measures of locomotor recovery (Rodemer et al, 2020 ). Presumably, PTPσ plays more than one role in the nervous system and the net effect of its knockdown may depend on the balance among its several roles in a given species and environment.…”

Section: Several Transmembrane Receptors Mediate Growth Suppression Omentioning

confidence: 99%

Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

Sami

Selzer

2020

Front. Cell. Neurosci.

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Axon growth inhibitors generated by reactive glial scars play an important role in failure of axon regeneration after CNS injury in mature mammals. Among the inhibitory factors, chondroitin sulfate proteoglycans (CSPGs) are potent suppressors of axon regeneration and are important molecular targets for designing effective therapies for traumatic brain injury or spinal cord injury (SCI). CSPGs bind with high affinity to several transmembrane receptors, including two members of the leukocyte common antigen related (LAR) subfamily of receptor protein tyrosine phosphatases (RPTPs). Recent studies demonstrate that multiple intracellular signaling pathways downstream of these two RPTPs mediate the growth-inhibitory actions of CSPGs. A better understanding of these signaling pathways may facilitate development of new and effective therapies for CNS disorders characterized by axonal disconnections. This review will focus on recent advances in the downstream signaling pathways of scar-mediated inhibition and their potential as the molecular targets for CNS repair.

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“…We have found several CSPG receptors in the lamprey genomic database (Zhang et al, 2014a ; Rodemer et al, 2020 ), and previously cloned the full-length of two receptor protein tyrosine phosphatases (RPTPs) protein tyrosine phosphatase sigma (PTPσ) and leukocyte antigen-related protein tyrosine phosphatase (LAR). Using ISH, we found that these CSPG receptors are expressed selectively in poorly regenerating/poorly surviving reticulospinal (RS) neurons both in uninjured animals and after SCI (Zhang et al, 2014a ).…”

Section: Introductionmentioning

confidence: 99%

“…These findings suggested that CSPGs and their receptors may play a role in both the poor intrinsic regenerative ability of some neurons and in their susceptibility to retrograde cell death. However, knockdown of the CSPG receptor PTPσ by morpholinos applied to the SC-TX impaired RS axon regeneration and neuronal survival after SCI (Rodemer et al, 2020 ). This result was inconsistent with the putative role of PTPσ in axon regeneration and neuronal survival after axotomy.…”

Section: Introductionmentioning

confidence: 99%

The Composition and Cellular Sources of CSPGs in the Glial Scar After Spinal Cord Injury in the Lamprey

Zhang

Jin

Rodemer

et al. 2022

Front. Mol. Neurosci.

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Axon regrowth after spinal cord injury (SCI) is inhibited by several types of inhibitory extracellular molecules in the central nervous system (CNS), including chondroitin sulfate proteoglycans (CSPGs), which also are components of perineuronal nets (PNNs). The axons of lampreys regenerate following SCI, even though their spinal cords contain CSPGs, and their neurons are enwrapped by PNNs. Previously, we showed that by 2 weeks after spinal cord transection in the lamprey, expression of CSPGs increased in the lesion site, and thereafter, decreased to pre-injury levels by 10 weeks. Enzymatic digestion of CSPGs in the lesion site with chondroitinase ABC (ChABC) enhanced axonal regeneration after SCI and reduced retrograde neuronal death. Lecticans (aggrecan, versican, neurocan, and brevican) are the major CSPG family in the CNS. Previously, we cloned a cDNA fragment that lies in the most conserved link-domain of the lamprey lecticans and found that lectican mRNAs are expressed widely in lamprey glia and neurons. Because of the lack of strict one-to-one orthology with the jawed vertebrate lecticans, the four lamprey lecticans were named simply A, B, C, and D. Using probes that distinguish these four lecticans, we now show that they all are expressed in glia and neurons but at different levels. Expression levels are relatively high in embryonic and early larval stages, gradually decrease, and are upregulated again in adults. Reductions of lecticans B and D are greater than those of A and C. Levels of mRNAs for lecticans B and D increased dramatically after SCI. Lectican D remained upregulated for at least 10 weeks. Multiple cells, including glia, neurons, ependymal cells and microglia/macrophages, expressed lectican mRNAs in the peripheral zone and lesion center after SCI. Thus, as in mammals, lamprey lecticans may be involved in axon guidance and neuroplasticity early in development. Moreover, neurons, glia, ependymal cells, and microglia/macrophages, are responsible for the increase in CSPGs during the formation of the glial scar after SCI.

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PTPσ Knockdown in Lampreys Impairs Reticulospinal Axon Regeneration and Neuronal Survival After Spinal Cord Injury

Cited by 7 publications

References 66 publications

Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

Advances in the Signaling Pathways Downstream of Glial-Scar Axon Growth Inhibitors

The Composition and Cellular Sources of CSPGs in the Glial Scar After Spinal Cord Injury in the Lamprey

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