TY  - JOUR
A1  - Dombert, Benjamin
A1  - Balk, Stefanie
A1  - Lüningschrör, Patrick
A1  - Moradi, Mehri
A1  - Sivadasan, Rajeeve
A1  - Saal-Bauernschubert, Lena
A1  - Jablonka, Sibylle
T1  - BDNF/trkB induction of calcium transients through Ca\(_{v}\)2.2 calcium channels in motoneurons corresponds to F-actin assembly and growth cone formation on β2-chain laminin (221)
JF  - Frontiers in Molecular Neuroscience
N2  - Spontaneous Ca\(^{2+}\) transients and actin dynamics in primary motoneurons correspond to cellular differentiation such as axon elongation and growth cone formation. Brain-derived neurotrophic factor (BDNF) and its receptor trkB support both motoneuron survival and synaptic differentiation. However, in motoneurons effects of BDNF/trkB signaling on spontaneous Ca\(^{2+}\) influx and actin dynamics at axonal growth cones are not fully unraveled. In our study we addressed the question how neurotrophic factor signaling corresponds to cell autonomous excitability and growth cone formation. Primary motoneurons from mouse embryos were cultured on the synapse specific, β2-chain containing laminin isoform (221) regulating axon elongation through spontaneous Ca\(^{2+}\) transients that are in turn induced by enhanced clustering of N-type specific voltage-gated Ca\(^{2+}\) channels (Ca\(_{v}\)2.2) in axonal growth cones. TrkB-deficient (trkBTK\(^{-/-}\)) mouse motoneurons which express no full-length trkB receptor and wildtype motoneurons cultured without BDNF exhibited reduced spontaneous Ca\(^{2+}\) transients that corresponded to altered axon elongation and defects in growth cone morphology which was accompanied by changes in the local actin cytoskeleton. Vice versa, the acute application of BDNF resulted in the induction of spontaneous Ca\(^{2+}\) transients and Ca\(_{v}\)2.2 clustering in motor growth cones, as well as the activation of trkB downstream signaling cascades which promoted the stabilization of β-actin via the LIM kinase pathway and phosphorylation of profilin at Tyr129. Finally, we identified a mutual regulation of neuronal excitability and actin dynamics in axonal growth cones of embryonic motoneurons cultured on laminin-221/211. Impaired excitability resulted in dysregulated axon extension and local actin cytoskeleton, whereas upon β-actin knockdown Ca\(_{v}\)2.2 clustering was affected. We conclude from our data that in embryonic motoneurons BDNF/trkB signaling contributes to axon elongation and growth cone formation through changes in the local actin cytoskeleton accompanied by increased Ca\(_{v}\)2.2 clustering and local calcium transients. These findings may help to explore cellular mechanisms which might be dysregulated during maturation of embryonic motoneurons leading to motoneuron disease.
KW  - growth cone
KW  - BDNF
KW  - trkB
KW  - Ca\(_{v}\)2.2
KW  - F-actin
KW  - motor axon
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159094
VL  - 10
IS  - 346
ER  - 
TY  - JOUR
A1  - Lüningschrör, Patrick
A1  - Binotti, Beyenech
A1  - Dombert, Benjamin
A1  - Heimann, Peter
A1  - Perez-Lara, Angel
A1  - Slotta, Carsten
A1  - Thau-Habermann, Nadine
A1  - von Collenberg, Cora R.
A1  - Karl, Franziska
A1  - Damme, Markus
A1  - Horowitz, Arie
A1  - Maystadt, Isabelle
A1  - Füchtbauer, Annette
A1  - Füchtbauer, Ernst-Martin
A1  - Jablonka, Sibylle
A1  - Blum, Robert
A1  - Üçeyler, Nurcan
A1  - Petri, Susanne
A1  - Kaltschmidt, Barbara
A1  - Jahn, Reinhard
A1  - Kaltschmidt, Christian
A1  - Sendtner, Michael
T1  - Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease
JF  - Nature Communications
N2  - Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.
KW  - autophagy
KW  - synaptic vesicles
KW  - Pleckstrin homology containing family member 5 (Plekhg5)
KW  - regulation
KW  - motoneuron disease
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170048
VL  - 8
IS  - 678
ER  -