Progressive Postnatal Motoneuron Loss in Mice Lacking GDF-15

Abstract

GDF-15 is a widely expressed distant member of the TGF-ß superfamily with prominent neurotrophic effects on midbrain dopaminergic neurons. We show here that GDF-15 deficient mice exhibit progressive postnatal losses of spinal, facial, and trigeminal motoneurons. This deficit reaches a ~20% maximum at 6 months and is accompanied by losses of motor axons and significant impairment of rotarod skills. Similarly, sensory neurons in dorsal root ganglia (L4, L5) are reduced by 20%, while sympathetic neurons are not affected. GDF-15 is expressed and secreted by Schwann cells, retrogradely transported along adult sciatic nerve axons, and promotes survival of axotomized facial neurons as well as cultured motor, sensory, and sympathetic neurons. Despite striking similarities in the GDF-15 and CNTF knockout phenotypes, expression levels of CNTF and other neurotrophic factors in the sciatic nerve were unaltered suggesting that GDF-15 is a genuine novel trophic factor for motor and sensory neurons.

The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice

“…Consistent with previous reports, 14 untreated Gdf15 homozygous null mice showed no obvious abnormalities other than a significant increase in body weight compared to wild-type mice (wild-type 26.3±2.1 g, n=16, vs. knockout 28.5±2.6 g, n=16; 8.2% increase, P=0.012;). There was no difference in hematologic parameters, plasma iron concentrations, or liver or spleen non-heme iron content between the two genotypes ( Table 1).…”

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

“…36 In mice, GDF-15 may function as a neurotrophic and neuroprotective cytokine, as GDF-15 knock-out mice show postnatal loss of motoneurons in spinal cord and brainstem motor nuclei and dorsal root ganglionic sensory neurons in superior cervical ganglion. 37 In this study, Strelau et al 37 also demonstrated that GDF-15 produced by Schwann cells promotes the survival of axotomized dopaminergic neurons both in vivo and in vitro. 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.…”

“…39 --41 However, GDF-15 deficient mice do not show abnormalities in the embryonic development and are fully viable and fertile. 37 Soucek et al 42 measured high levels of GDF-15 in seminal plasma from male donors irrespective of fertility status. Seminal GDF-15 does not appear to influence sperm cell viability or interact with vaginal or cervical cells, but it is capable of inhibiting the proliferation of peripheral blood mononuclear cells in a manner similar to TGF-b-1, but at higher effective concentrations.…”

Bioactivity and Prognostic Significance of Growth Differentiation Factor GDF15 Secreted by Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma

“…Although further work need to be done to characterize GDF15 biology, we suggest that GDF15 participates in the control of minimal residual disease, possibly by maintaining in a chemoprotective niche an undetectable pool of multiple myeloma cells causing the relapse. Because of the moderately minor phenotype displayed by GDF15-knockout mice (49,50), therapeutic strategy specifically targeting GDF15 might be conceivable. In this regard, future studies from our laboratory will assess GDF15 as a novel target for therapeutic strategies in multiple myeloma.…”