Regulation of GDF-15, a distant TGF-β superfamily member, in a mouse model of cerebral ischemia.
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.
Institute for Pharmaceutical Biotechnology, University of Applied Science Biberach, Biberach/Riss, Germany.
Katharina
K
Schindowski
Oliver
O
von Bohlen und Halbach
Jens
J
Strelau
Dirk A
DA
Ridder
Oliver
O
Herrmann
Andreas
A
Schober
Markus
M
Schwaninger
Klaus
K
Unsicker
D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D002544:Cerebral Infarction / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000378:metabolism; D023421:Models, Animal; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D055436:Growth Differentiation Factor 15; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta