Dogs can be used as a translational animal model to close the gap between basic discoveries in rodents and clinical trials in humans. The present study compared the species-specific properties of satellite glial cells (SGCs) of canine and murine dorsal root ganglia (DRG) in situ and in vitro using light microscopy, electron microscopy, and immunostainings. The in situ expression of CNPase, GFAP, and glutamine synthetase (GS) has also been investigated in simian SGCs. In situ, most canine SGCs (>80%) expressed the neural progenitor cell markers nestin and Sox2. CNPase and GFAP were found in most canine and simian but not murine SGCs. GS was detected in 94% of simian and 71% of murine SGCs, whereas only 44% of canine SGCs expressed GS. In vitro, most canine (>84%) and murine (>96%) SGCs expressed CNPase, whereas GFAP expression was differentially affected by culture conditions and varied between 10% and 40%. However, GFAP expression was induced by bone morphogenetic protein 4 in SGCs of both species. Interestingly, canine SGCs also stimulated neurite formation of DRG neurons. These findings indicate that SGCs represent an exceptional, intermediate glial cell population with phenotypical characteristics of oligodendrocytes and astrocytes and might possess intrinsic regenerative capabilities in vivo.

GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-gangliosidosis in a new Glb1 knockout mouse model. Glb1−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material GM1, GA1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.

certain growth factors 23. Gangliosides are sialic acid-containing glycosphingolipids that can be found in different cellular membranes. In the CNS gangliosides account for up to 10% of the total lipid content in neurons 24. They are involved in intercellular communication, cellular differentiation, neuronal development, and regeneration 25-28 due to their capacity to modulate Ca 2+ influx and their influence on the function of receptors for muscarinic acetylcholine, serotonin, glutamine, neurotransmitters, and neurotrophic factors 29. Cellular gangliosides concentrate in lipid microdomains termed lipid rafts, which are signaling platforms rich in cholesterol and glycosphingolipids and contain amongst others high affinity tropomyosin-related kinase (Trk) and low affinity neurotrophin receptors (p75 NTR) 30-32. These receptors are activated by nerve growth factor (NGF) and other neurotrophic factors and have a strong impact on neuronal development, maintenance, and survival as well as memory formation and storage 33,34. Anti-G M1 antibodies modulate the membrane-associated sphingomyelin metabolism by altering neutral sphingomyelinase activity thereby inhibiting NGF action on rat pheochromocytoma (PC12) cells 35,36. G M1 and NGF protect primary cultured rat embryonic dorsal root ganglia (DRG) and spinal cord neurons from glutamate-induced excitotoxicity 37,38. Both molecules may function by modulating Ca 2+ homeostasis, maintaining normal mitochondrial membrane potential or by promoting the mRNA expression of neuronal proteins such as growth associated protein 43 and neurofilaments (NFs) 38,39. G M1 also protects rats against high altitude cerebral edema by suppressing oxidative stress and production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α 40. Nevertheless, another study using an ischemia/reperfusion model in rats demonstrated that G M1 neuroprotection seems to be dependent on p75 NTR 41. Exogenous gangliosides also directly interact with growth factors such as basic fibroblast growth factor (FGF2) and inhibit FGF receptor binding 42,43. Moreover, G M1 can inhibit FGF2-mediated effects by acting on the same intracellular signaling molecules. For instance, FGF2 stimulates the activity of glycogen synthase kinase 3 (GSK3) in proliferating adult rat hippocampal progenitor cells, whereas G M1 prevents GSK3 activation in organotypic hippocampal slice cultures 44,45. In contrast, cell-associated G M1 has been described to act as a functional co-receptor for FGF2 43. Despite its name, FGF2 plays an essential role in neurogenesis, differentiation, axonal branching, and neuron survival in various types of brain and peripheral nerve lesions 46,47. FGF2 also stimulates the proliferation of neuronal precursor cells isolated from postnatal murine DRGs 48. The ability of adult rat ganglion cells to regrow axons in vitro can be influenced by FGF2 and G M1 49. Neurotrophic effects of FGF2 seem to be also mediated by soluble mediators released from glial cells 50. Summarized, NGF, FGF2 and gangliosides such as G M1 ...

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