Developmental motoneuron cell death and neurotrophic factors

Sendtner, Michael; Pei, Geng; Beck, Marcus; Schweizer, Ulrich; Wiese, Stefan

doi:10.1007/s004410000217

Cited by 124 publications

(97 citation statements)

References 101 publications

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“…Motoneurons are polytrophic and show protection mediated by a variety of angiogenic growth factors, such as VEGF and FGF, via the expression of high-affinity receptors such as flk1, flt1, and FGFR1 (Gonzalez et al, 1995;Sendtner et al, 2000;Lambrechts and Carmeliet, 2006;Poesen et al, 2008). Most neurons require signaling endosomes to ensure sufficient prosurvival signaling reaches the nucleus (Howe and Mobley, 2005).…”

Section: Discussionmentioning

confidence: 99%

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Skorupa

King²,

Aparicio³

et al. 2012

J. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS.

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Section: Discussionmentioning

confidence: 99%

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Skorupa

King²,

Aparicio³

et al. 2012

J. Neurosci.

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“…For example, neurotrophic factors are critical for the survival of spinal motor neurons [34][35][36]. It is possible that SMN disrupts the responses of motor neurons to trophic factors, which needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Wang

Zhang

2012

Cell Res

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Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-∆7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

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“…The most common hypothesis underlying the survival of MNs during PCD is that these cells compete successfully for limited amounts of trophic factor from the target, whereas the cells that lose in this competition ultimately die (Cunningham, 1982;Oppenheim, 1991;Sendtner et al, 2000;Yuan and Yankner, 2000). Underscoring the critical nature of the target in the regulation of MN survival are studies in which the unilateral extirpation of a limb results in the loss of nearly (ϳ90%) all of the MNs ipsilateral to the lesion.…”

Section: Trophic Sources For Mnsmentioning

confidence: 99%

“…During PCD, which occurs between embryonic day 5 (E5) and E12 in the chick embryo, 40 -50% of the MNs that are originally born die by a process thought to be the direct result of a competition for a limited supply of target-derived trophic support (Cunningham, 1982;Oppenheim, 1991;Sendtner et al, 2000;Yuan and Yankner, 2000). Classically, the role of the target has been demonstrated by experimental manipulation of its size.…”

Section: Introductionmentioning

confidence: 99%

“…Similar to MEx, media conditioned by muscle cells and myotubes promote neurite outgrowth and MN survival both in vitro and in vivo (Henderson et al, 1981;Calof and Reichardt, 1984;Eagleson and Bennett, 1986;Petruzzelli and Hughes, 1989;Oppenheim et al, 1993;Arce et al, 1998). Both of these protein mixtures contain multiple putative target-derived trophic factors that have been identified to rescue MNs both in vitro and in vivo [e.g., BDNF, neurotrophin 3 (NT3), NT4/5, glial cell line-derived neurotrophic factor (GDNF), CNTF, HGF (hepatic growth factor), EGF (epidermal growth factor), FGF, IGF-1, and cardiotrophin-1 among others] (Oppenheim, 1996;Henderson et al, 1998;Sendtner et al, 2000). MNs are a unique neuronal population in that they not only require multiple factors to maximally sustain their survival, but they are insensitive to the prototypical neurotrophin nerve growth factor (NGF), because they are deficient in the tyrosine receptor kinase A (TrkA) receptor (Oppenheim et al, 1993;Yan et al, 1993;Nishi, 1994;Oppenheim, 1996;Sendtner et al, 1996;Curtis et al, 1998;Gould and Oppenheim, 2004;Ricart et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Astrocyte and Muscle-Derived Secreted Factors Differentially Regulate Motoneuron Survival

Taylor¹,

Gifondorwa²,

Newbern³

et al. 2007

J. Neurosci.

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During development, motoneurons (MNs) undergo a highly stereotyped, temporally and spatially defined period of programmed cell death (PCD), the result of which is the loss of 40 -50% of the original neuronal population. Those MNs that survive are thought to reflect the successful acquisition of limiting amounts of trophic factors from the target. In contrast, maturation of MNs limits the need for target-derived trophic factors, because axotomy of these neurons in adulthood results in minimal neuronal loss. It is unclear whether MNs lose their need for trophic factors altogether or whether, instead, they come to rely on other cell types for nourishment. Astrocytes are known to supply trophic factors to a variety of neuronal populations and thus may nourish MNs in the absence of target-derived factors. We investigated the survival-promoting activities of muscle-and astrocyte-derived secreted factors and found that astrocyteconditioned media (ACM) was able to save substantially more motoneurons in vitro than muscle-conditioned media (MCM). Our results indicate that both ACM and MCM are significant sources of MN trophic support in vitro and in ovo, but only ACM can rescue MNs after unilateral limb bud removal. Furthermore, we provide evidence suggesting that MCM facilitates the death of a subpopulation of MNs in a p75 NTR -and caspase-dependent manner; however, maturation in ACM results in MN trophic independence and reduced vulnerability to this negative, pro-apoptotic influence from the target.

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Developmental motoneuron cell death and neurotrophic factors

Cited by 124 publications

References 101 publications

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Astrocyte and Muscle-Derived Secreted Factors Differentially Regulate Motoneuron Survival

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