TGF-β superfamily members, ActivinA and TGF-β1, induce apoptosis in oligodendrocytes by different pathways

Schulz, Ramona; Vogel, Tanja; Dressel, Ralf; Krieglstein, Kerstin

doi:10.1007/s00441-008-0714-5

Cited by 18 publications

(12 citation statements)

References 36 publications

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“…Reports also suggest potential roles for Tgfβ and Activin ligands in repair in demyelinating models (Hinks and Franklin, 1999;John et al, 2002;Miron et al, 2013). Interestingly, however, our data do not match a report in Oli-Neu cells that implicated ActA in the causation of apoptosis (Schulz et al, 2008). Although ActA is not found in the developing CNS (Feijen et al, 1994), in our own experiments in primary OLPs we have found that it produces a close match to the effects of ActB, and so the source of this dichotomy is not immediately clear.…”

Section: Roles Of Tgfβ and Activin Ligands In Oligodendrocyte Developcontrasting

confidence: 99%

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

et al. 2014

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In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLPneuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb −/− embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3 −/− mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation.

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Section: Roles Of Tgfβ and Activin Ligands In Oligodendrocyte Developcontrasting

confidence: 99%

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

et al. 2014

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“…The TGFβ superfamily has been shown to play a role in inducing apoptosis [28], [29]. In the case of freemartins, where female embryos were exposed to anti-Müllerian hormone, a member of the TGFβ superfamily, germ cell loss was observed [30], [31].…”

Section: Resultsmentioning

confidence: 99%

WNT4/β-Catenin Pathway Maintains Female Germ Cell Survival by Inhibiting Activin βB in the Mouse Fetal Ovary

2010

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Female germ cells are essential for organogenesis of the ovary; without them, ovarian follicles do not form and functional and structural characteristics of the ovary are lost. We and others showed previously that when either Wnt4 or β-catenin was inactivated in the fetal ovary, female germ cells underwent degeneration. In this study, we set out to understand whether these two factors belong to the same pathway and how they maintain female germ cell survival. We found that activation of β-catenin in somatic cells in the Wnt4 knockout ovary restored germ cell numbers, placing β-catenin downstream of WNT4. In the absence of Wnt4 or β-catenin, female germ cells entered meiosis properly; however, they underwent apoptosis afterwards. Activin βB (Inhbb), a subunit of activins, was upregulated in the Wnt4 and β-catenin knockout ovaries, suggesting that Inhbb could be the cause for the loss of female germ cells, which are positive for activin receptors. Indeed, removal of Inhbb in the Wnt4 knockout ovaries prevented female germ cells from undergoing degeneration. We conclude that WNT4 maintains female germ cell survival by inhibiting Inhbb expression via β-catenin in the somatic cells. Maintenance of female germ cells hinge upon a delicate balance between positive (WNT4 and β-catenin) and negative (activin βB) regulators derived from the somatic cells in the fetal ovary.

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“…Previous studies have investigated the potential pathomechanisms underlying oligodendrocyte cell death following a hypoxic/ischemic or traumatic insult [9, 10, 30, 31]. Following TBI, studies have reported that oligodendrocyte cells in the subcortical white matter undergo apoptotic cell death [7, 29, 32].…”

Section: Discussionmentioning

confidence: 99%

Oligodendrocyte vulnerability following traumatic brain injury in rats

Lotocki

Vaccari

Alonso

et al. 2011

Neuroscience Letters

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Experimental and clinical findings demonstrate that traumatic brain injury (TBI) results in injury to both gray and white matter structures. The purpose of this study was to document patterns of oligodendrocyte vulnerability to TBI. Sprague Dawley rats underwent sham operated procedures or moderate fluid percussion brain injury. Animals were perfusion-fixed for quantitative immunohistochemical analysis at 3 (n=9) or 7 (n=9) days post-surgery. Within the ipsilateral external capsule and corpus callosum, numbers of APC-CC1 immunoreactive oligodendrocytes were significantly decreased at 3 or 7 days post-TBI compared to sham rats (p<0.03). At both posttraumatic survival periods, double-labeling studies indicated that oligodendrocytes showed increased Caspase 3 activation compared to sham. These data demonstrate regional patterns of oligodendrocyte vulnerability after TBI and that oligodendrocyte cell loss may be due to Caspase 3-mediated cell death mechanisms. Further studies are needed to test therapeutic interventions that prevent trauma-induced oligodendrocyte cell death, subsequent demyelination and circuit dysfunction.

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TGF-β superfamily members, ActivinA and TGF-β1, induce apoptosis in oligodendrocytes by different pathways

Cited by 18 publications

References 36 publications

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

WNT4/β-Catenin Pathway Maintains Female Germ Cell Survival by Inhibiting Activin βB in the Mouse Fetal Ovary

Oligodendrocyte vulnerability following traumatic brain injury in rats

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