Regulation of GDF-15, a distant TGF-β superfamily member, in a mouse model of cerebral ischemia

Abstract

GDF-15 is a novel distant member of the TGF-β superfamily and is widely distributed in the brain and peripheral nervous system. We have previously reported that GDF-15 is a potent neurotrophic factor for lesioned dopaminergic neurons in the substantia nigra, and that GDF-15-deficient mice show progressive postnatal losses of motor and sensory neurons. We have now investigated the regulation of GDF-15 mRNA and immunoreactivity in the murine hippocampal formation and selected cortical areas following an ischemic lesion by occlusion of the middle cerebral artery (MCAO). MCAO prominently upregulates GDF-15 mRNA in the hippocampus and parietal cortex at 3 h and 24 h after lesion. GDF-15 immunoreactivity, which is hardly detectable in the unlesioned brain, is drastically upregulated in neurons identified by double-staining with NeuN. NeuN staining reveals that most, if not all, neurons in the granular layer of the dentate gyrus and pyramidal layers of the cornu ammonis become GDF-15-immunoreactive. Moderate induction of GDF-15 immunoreactivity has been observed in a small number of microglial cells identified by labeling with tomato lectin, whereas astroglial cells remain GDF-15-negative after MCAO. Comparative analysis of the size of the infarcted area after MCAO in GDF-15 wild-type and knockout mice has failed to reveal significant differences. Together, our data substantiate the notion that GDF-15 is prominently upregulated in the lesioned brain and might be involved in orchestrating post-lesional responses other than the trophic support of neurons.

Growth Differentiation Factor 15 Plasma Levels and Outcome after Ischemic Stroke

“…In support of this hypothesis, GDF-15 is strongly produced at the lesion site after experimental brain injury in rodents [12,13,14]. Considering that GDF-15 levels declined by only 8% from day 1 to day 7 in our study, the majority of circulating GDF-15 in patients with ischemic stroke is probably not derived from the injured brain but related to underlying atherosclerotic disease burden as discussed above [8].…”

“…As shown in rats, GDF-15 is strongly expressed by macrophages, activated microglial cells, and neurons after cortical brain cryoinjury [12,13]. In a model of murine middle cerebral artery occlusion, GDF-15 has been found to be upregulated in the hippocampus and parietal cortex 3 and 24 h after the onset of ischemia [14]. …”

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

“…Further investigation in ischemia-induced brain lesions showed strong and rapid induction of GDF --15 mRNA in neurons and partially in microglial cells; however, a comparison of identically lesioned GDF-15-knock-out and wild-type mice did not reveal a significant difference in infarct area, suggesting a role for GDF-15 in post-lesion adaptation and regeneration rather than general protection or neuronal tissue nutrition. 38 In addition to tissue regeneration and repair, GDF-15 is involved in human embryonic development, as it is highly expressed in the placenta during pregnancy, and low levels of GDF-15 in the first weeks of gestation correlate with a higher risk of miscarriage. 39 --41 However, GDF-15 deficient mice do not show abnormalities in the embryonic development and are fully viable and fertile.…”

Growth/differentiation factor-15 and its role in peripheral nervous system lesion and regeneration

“…However, the protein levels do not follow the same pattern (Fig 3.1 C D), possibly resulting from the mild change in transcriptional levels. In the brain, GDF-15 is highly expressed predominantly by the neurons in both cortex cryolesion and cerebral ischemia models, but also expressed by a small proportion of microglial cells (Schindowski et al, 2011;Schober et al, 2001). Another study on optic nerve…”