Astrocyte and Muscle-Derived Secreted Factors Differentially Regulate Motoneuron Survival

Abstract

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.

Ciliary Neurotrophic Factor-treated Astrocyte Conditioned Medium Regulates the L-type Calcium Channel Activity in Rat Cortical Neurons

“…Experimentally, some effects of astrocytes on neurons in vitro may be mimicked by exposing to ACM. For instance, ACM could protect the neurons against damages and support the survival of neurons [23][24][25]. So, ACM is considered a meaningful medium in studying the actions of astrocytes on neurons.…”

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

“…Activated microglia, in turn, secrete proinflammatory peptides, nitric oxide (NO), and excitotoxins that further induce astrocytosis or aggravate neuronal damage, therefore perpetuating and amplifying a local pathogenic process (56). Recent evidence indicates the existence of mechanisms by which activated astrocytes may contribute either to the death of neurons or to their survival in response to damage (7,106,132). Understanding these processes and the interaction between neurons and glia may help to explain the induction and the propagation of motor-neuron loss in ALS.…”

Axonal Degeneration in Motor Neuron Disease

“…Though commonly thought of as a source of target-derived trophic support, muscle was recently shown to trigger motor neuron death in certain developmental contexts, which may or may not be relevant to what goes on during motor neuron disease [113] . Increased expression of Nogo-A, an inhibitor of neurite outgrowth, has also been seen in muscle of SOD1 mutant mice and in patients with sporadic ALS, suggesting a possible role for muscle in inhibiting regenerative sprouting [114] .…”