Transforming growth factor‐β1 primes proliferating adult neural progenitor cells to electrophysiological functionality

Kraus, Sabrina; Lehner, Bernadette; Reichhart, Nadine; Couillard‐Després, Sébastien; Wagner, Katrin; Bogdahn, Ulrich; Aigner, Ludwig; Strauß, Olaf

doi:10.1002/glia.22551

Cited by 10 publications

(8 citation statements)

References 41 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At the same time, we demonstrate here that TGF‐β1 reduces cell death in neurospheres and promotes the expression of neuronal‐specific gene DCX and the electrophysiological functionality of NPCs in the presence of EGF and FGF. The latter was confirmed by a more detailed electrophysiology study demonstrating the TGF‐β1 primed neural progenitors under proliferation conditions to functional maturation with firing action potentials . In summary, TGF‐β1 is promoting neuronal differentiation/survival as well as neural stem cell quiescence.…”

Section: Discussionmentioning

confidence: 70%

TGF‐beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons

Kandasamy

Lehner

Kraus

et al. 2014

J Cellular Molecular Medi

Self Cite

104

View full text Add to dashboard Cite

Members of the transforming growth factor (TGF)-β family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF-β signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF-β1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF-β1 under a tetracycline regulatable Ca-Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF-β1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF-β1 signalling in adult NPCs. The results demonstrate that TGF-β1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF-β1 in ageing and neurodegenerative diseases, TGF-β1 signalling presents a molecular target for future interventions in such conditions.

show abstract

Section: Discussionmentioning

confidence: 70%

TGF‐beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons

Kandasamy

Lehner

Kraus

et al. 2014

J Cellular Molecular Medi

Self Cite

104

View full text Add to dashboard Cite

show abstract

“…A similar dual role during adult neurogenesis has already been suggested for TGF-β1 [32]. We have recently demonstrated that treatment of adult neuronal progenitor cells with TGF-β1 increased LTCC activity in these cells [53]. Moreover, TGF-β1 elevated Cav1.3 mRNA expression in cerebellar granular neurons in vitro [54].…”

Section: Discussionmentioning

confidence: 84%

The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions

et al. 2015

Self Cite

View full text Add to dashboard Cite

L-type voltage gated Ca(2+) channels (LTCCs) are widely expressed within different brain regions including the hippocampus. The isoforms Cav1.2 and Cav1.3 have been shown to be involved in hippocampus-dependent learning and memory, cognitive functions that require proper hippocampal neurogenesis. In vitro, functional LTCCs are expressed on neuronal progenitor cells, where they promote neuronal differentiation. Expression of LTCCs on neural stem and progenitor cells within the neurogenic regions in the adult brain in vivo has not been examined so far, and a contribution of the individual isoforms Cav1.2 and Cav1.3 to adult neurogenesis remained to be clarified. To reveal the role of these channels we first evaluated the expression patterns of Cav1.2 and Cav1.3 in the hippocampal dentate gyrus and the subventricular zone (SVZ) in adult (2- and 3-month old) and middle-aged (15-month old) mice on mRNA and protein levels. We performed immunohistological analysis of hippocampal neurogenesis in adult and middle-aged Cav1.3(-/-) mice and finally addressed the importance of Cav1.3 for hippocampal function by evaluating spatial memory and depression-like behavior in adult Cav1.3(-/-) mice. Our results showed Cav1.2 and Cav1.3 expression at different stages of neuronal differentiation. While Cav1.2 was primarily restricted to mature NeuN(+) granular neurons, Cav1.3 was expressed in Nestin(+) neural stem cells and in mature NeuN(+) granular neurons. Adult and middle-aged Cav1.3(-/-) mice showed severe impairments in dentate gyrus neurogenesis, with significantly smaller dentate gyrus volume, reduced survival of newly generated cells, and reduced neuronal differentiation. Further, Cav1.3(-/-) mice showed impairment in the hippocampus dependent object location memory test, implicating Cav1.3 as an essential element for hippocampus-associated cognitive functions. Thus, modulation of LTCC activities may have a crucial impact on neurogenic responses and cognition, which should be considered for future therapeutic administration of LTCCs modulators.

show abstract

“…Besides, it is well documented that TGF-beta1 could alter the expression of many different integrins, cell adhesion molecules, extracellular matrix and other factors important for cellular migration and, in addition, exerts growth-inhibitory responses in normal cells, but induces migration and invasion of neoplasms [58]. Also, TGF-beta1 blocks proliferation of neural progenitor cells and promotes stem cell quiescence and neuronal survival / differentiation [36,59]. Our present study supports the hypothesis that TGF-beta1 might be a crucial factor regulating the migration of DCX positive neuroblast, as we have noticed the appearance of pSmad2 in the nucleus of DCX positive neuroblasts in the RMS of WT rats and also in the striatum of tgHD rat.…”

Section: Discussionmentioning

confidence: 99%

Reduction in Subventricular Zone-Derived Olfactory Bulb Neurogenesis in a Rat Model of Huntington’s Disease Is Accompanied by Striatal Invasion of Neuroblasts

et al. 2015

Self Cite

View full text Add to dashboard Cite

Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene (HTT). The primary neuropathology of HD has been attributed to the preferential degeneration of medium spiny neurons (MSN) in the striatum. Reports on striatal neurogenesis have been a subject of debate; nevertheless, it should be considered as an endogenous attempt to repair the brain. The subventricular zone (SVZ) might offer a close-by region to supply the degenerated striatum with new cells. Previously, we have demonstrated that R6/2 mice, a widely used preclinical model representing an early onset HD, showed reduced olfactory bulb (OB) neurogenesis but induced striatal migration of neuroblasts without affecting the proliferation of neural progenitor cell (NPCs) in the SVZ. The present study revisits these findings, using a clinically more relevant transgenic rat model of late onset HD (tgHD rats) carrying the human HTT gene with 51 CAG repeats and mimicking many of the neuropathological features of HD seen in patients. We demonstrate that cell proliferation is reduced in the SVZ and OB of tgHD rats compared to WT rats. In the OB of tgHD rats, although cell survival was reduced, the frequency of neuronal differentiation was not altered in the granule cell layer (GCL) compared to the WT rats. However, an increased frequency of dopamenergic neuronal differentiation was noticed in the glomerular layer (GLOM) of tgHD rats. Besides this, we observed a selective proliferation of neuroblasts in the adjacent striatum of tgHD rats. There was no evidence for neuronal maturation and survival of these striatal neuroblasts. Therefore, the functional role of these invading neuroblasts still needs to be determined, but they might offer an endogenous alternative for stem or neuronal cell transplantation strategies.

show abstract

Transforming growth factor‐β1 primes proliferating adult neural progenitor cells to electrophysiological functionality

Cited by 10 publications

References 41 publications

TGF‐beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons

TGF‐beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons

The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions

Reduction in Subventricular Zone-Derived Olfactory Bulb Neurogenesis in a Rat Model of Huntington’s Disease Is Accompanied by Striatal Invasion of Neuroblasts

Contact Info

Product

Resources

About