Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway

Nishimune, Hiroshi; Vasseur, Sophie; Wiese, Stefan; Birling, Marie‐Christine; Holtmann, Bettina; Sendtner, Michael; Iovanna, Juan; Henderson, Chris

doi:10.1038/35046558

Cited by 140 publications

(145 citation statements)

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“…The expression of Reg-2 in intact spinal cord tissue of E18 rats has been detected in our previous studies, which is consistent with earlier reports of Reg-2 using whole-mount in situ hybridization techniques in E18 rats (Nishimune et al, 2000). Reg-2 expression can be detected in the neural cells from both ventral and dorsal horn.…”

Section: Discussionsupporting

confidence: 92%

“…PAP also has antibacterial and antiapoptotic properties, which can against pancreatitis and liver injury (Terazono et al, 1988;Simon et al, 2003). Previous studies also revealed the potential role of PAP in the development and regeneration of the central and peripheral nervous system (Livesey et al, 1997;Nishimune et al, 2000).…”

mentioning

confidence: 99%

“…The expression is transient and declines in postnatal developmental stages and is consequently absent in normal adults. In rats, Reg-2 is also constitutively expressed in subpopulations of motor neurons during development (Nishimune et al, 2000). This expression is driven by cytokines of the interleukin-6 family, including ciliary neurotrophic factor (CNTF), leukemia inhibitory factor, and cardiotrophin (Dusetti et al, 1995;Livesey et al, 1997;Averill et al, 2002;Schweizer et al, 2002).…”

mentioning

confidence: 99%

“…This expression is driven by cytokines of the interleukin-6 family, including ciliary neurotrophic factor (CNTF), leukemia inhibitory factor, and cardiotrophin (Dusetti et al, 1995;Livesey et al, 1997;Averill et al, 2002;Schweizer et al, 2002). Finally, Reg-2 also acts as a neurotrophic factor that is an essential intermediary via the CNTF pathway to support the survival of motor neurons during development (Nishimune et al, 2000).…”

mentioning

confidence: 99%

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Effects of Reg‐2 on Survival of Spinal Cord Neurons In Vitro

Fang

Huang

Shao

et al. 2010

The Anatomical Record

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Regeneration gene protein 2 (Reg-2) is a small secreted protein expressed in motor and sensory neurons of spinal cord during developmental stages and following injury of peripheral nerves. Reg-2 appears to act as a neurotrophic factor and protects injured neurons from death during regeneration. To illustrate these potential protective effects in vitro, we investigated the blocking effects of Reg-2 antibodies on the survival of primary cultured spinal cord neurons and astrocytes, as well as on neurite outgrowth. In addition, the effects of Reg-2 in neuron injury models induced by peroxide and mitochondrial poisoning were assessed. Our results showed that Reg-2 antibody markedly reduced survival and neurite outgrowth from neurons, whereas astrocyte survival was unaffected. Addition of Reg-2 into the culture medium had no effect on neuron survival or neurite outgrowth. However, the addition of the Reg-2 into culture media after peroxide treatment or cellular hypoxia insult induced by mitochondrial poisoning can reduce lactate dehydrogenase release levels and cell death. Thus, the data suggests that Reg-2 is essential for the survival and neurite outgrowth of developing spinal cord neurons but not the survival of glial cells, and that Reg-2 plays protective effects on spinal cord neurons against injury in vitro. Anat Rec, 293:464-476, 2010. V V C 2010 Wiley-Liss, Inc.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of Reg‐2 on Survival of Spinal Cord Neurons In Vitro

Fang

Huang

Shao

et al. 2010

The Anatomical Record

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“…First, it could be considered that the deficit of lithostathine level observed in AD-like aged animals in comparison to healthy elderly mouse lemurs and the location of amyloid plaques observed in areas devoid of lithostathine-reactive neurons suggest a protective role of lithostathine, as previously reported in peripheral tissues (Orelle et al, 1992;Sekikawa et al, 2005;Viterbo et al, 2009). This function may be related to a putative involvement of lithostathine in plasticity mechanisms as suggested by De La Monte et al (de la Monte et al, 1990) or evidenced for an homologous regenerating protein Reg2 in central nervous system (Nishimune et al, 2000). In contrast, based on the pro-inflammatory property of lithostathine and its link to pro-inflammatory cytokines overexpression (Duplan et al, 2001), we propose that accumulation of lithostathine in the brain would also be an indirect consequence of peculiar chronic inflammatory status during aging (Franceschi and Bonafe, 2003;Giunta et al, 2008;Giunta, 2006).…”

Section: Discussionmentioning

confidence: 62%

Distribution of lithostathine in the mouse lemur brain with aging and Alzheimer's-like pathology

Marchal¹,

Givalois²,

Verdier³

et al. 2012

Neurobiology of Aging

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We analyzed the cellular distribution of the pancreatic inflammatory protein lithostathine and its receptor EXTL3 in the brain of the lemurian primate Microcebus murinus which develops amyloid deposits along with aging. In adult animals (2-4.5 year-old), lithostathine and EXTL3 immunoreactivities were largely distributed in the whole brain, and more intensively in almost all cortical layers and hippocampal formation. Lithostathine was observed in the perikarya and neurites of cortical neurons but also in glial cells in the border of the ventricle and the corpus callosum.In healthy aged animals (8-13 year-old), highest densities of lithostathine containing cells were observed, mainly in occipital and parietal cortex. In aged animals with A deposits, the increase in lithostathine immunoreactivity was lower as compared with aged animals. Noteworthly, lithostathine-immunopositive cells did almost never colocalize with A plaques. In conclusion, lithostathine immunoreactivity in adult Microcebus murinus appeared ubiquitous and particularly in visual, sensorial and cognitive brain areas. Immunoreactivity increased with aging and appeared markedly affect in neuropathological conditions. Its possible neuroprotection or neurodegeneration role in Alzheimer pathology deserves therefore to be investigated.

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HIP/PAP prevents excitotoxic neuronal death and promotes plasticity

Haldipur

Dupuis

Degos

et al. 2014

Ann Clin Transl Neurol

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ObjectivesExcitotoxicity plays a significant role in the pathogenesis of perinatal brain injuries. Among the consequences of excessive activation of the N-methyl-d-aspartate (NMDA)-type glutamate are oxidative stress caused by free radical release from damaged mitochondria, neuronal death and subsequent loss of connectivity. Drugs that could protect nervous tissue and support regeneration are attractive therapeutic options. The hepatocarcinoma intestine pancreas protein/pancreatitis-associated protein I (HIP/PAP) or Reg3α, which is approved for clinical testing for the protection and regeneration of the liver, is upregulated in the central nervous system following injury or disease. Here, we examined the neuroprotective/neuroregenerative potential of HIP/PAP following excitotoxic brain injury.MethodsWe studied the expression of HIP/PAP and two of its putative effectors, cAMP-regulated phosphoprotein 19 (ARPP19) and growth-associated protein 43 (GAP-43), in the neonatal brain, and the protective/regenerative properties of HIP/PAP in three paradigms of perinatal excitotoxicity: intracerebral injection of the NMDA agonist ibotenate in newborn pups, a pediatric model of traumatic brain injury, and cultured primary cortical neurons.ResultsHIP/PAP, ARPP19, and GAP-43 were expressed in the neonatal mouse brain. HIP/PAP prevented the formation of cortical and white matter lesions and reduced neuronal death and glial activation following excitotoxic insults in vivo. In vitro, HIP/PAP promoted neuronal survival, preserved neurite complexity and fasciculation, and protected cell contents from reactive oxygen species (ROS)-induced damage.InterpretationHIP/PAP has strong neuroprotective/neuroregenerative potential following excitotoxic injury to the developing brain, and could represent an interesting therapeutic strategy in perinatal brain injury.

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Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway

Cited by 140 publications

References 50 publications

Effects of Reg‐2 on Survival of Spinal Cord Neurons In Vitro

Effects of Reg‐2 on Survival of Spinal Cord Neurons In Vitro

Distribution of lithostathine in the mouse lemur brain with aging and Alzheimer's-like pathology

HIP/PAP prevents excitotoxic neuronal death and promotes plasticity

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