Development and regeneration of mesencephalic dopaminergic neurons
Zusammenfassung der Projektergebnisse
Dopaminergic neurons from the substantia nigra are important regulators of corticostriatal neurotransmission. Their loss leads to, inter alia, impaired motor functions described as Parkinson’s disease. A detailed knowledge of the developmental differentiation pathway and phenotype characteristics of mesencephalic dopaminergic neurons innervating the striatum, as well as their long-term requirement in terms of survival and adult maintenance are crucial for a better understanding of the vulnerability of these neurons in Parkinson’s disease. Work of the first funding period has documented that transforming growth factors beta (TGF-β), TGF-β2 and -β3 are required for induction and specification of dopaminergic neurons as well as for their survival during development in the chick embryo. In continuation, the current project focused on the precise analyses of the impairment caused upon loss of TGF-ß signalling during the developmental time window required for induction and specification of dopaminergic neurons in mice (En1-TßR-IIflox/flox) as well as the functional characterization of newly identified molecules within the developmental ventral midbrain. Although the analyses of the TβR-IIflox/en-1 mice turned out to be much more complicated as anticipated there is clear evidence for the cell-specific loss of TGF-β signaling in En1- expressing cells. Further molecular characterization presents evidence of a TGF-β dependent regulation of Ca2+ homeostasis. Another aspect that has been overlooked for some time is the role of microglia in the regulation of neuron development, maintenance and de-/regeneration. Particularly in the midbrain the amount of microglia cells is specifically high. Our analyses document an important role of microglia in midbrain neuron development and maintenance, as well as TGF-β as a key player in activating alternative microglia activation via IL-4 and IL-6 mediated protection against MPP+-induced neurodegenertation. In summary, we can conclude that TGF-β plays a key role in orchestrating the response of DAergic neurons to its environment. However, much more and detailed analyses is required to understand the full profile of TGF-β signalling for the development and regeneration of DAergic neurons.
Projektbezogene Publikationen (Auswahl)
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(2011) More than being protective: functional roles for TGF-β/activin signaling pathways at central synapses. Trends Neurosci. 34(8):421-9
Krieglstein K, Zheng F, Unsicker K, Alzheimer C
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(2012) IL6 protects MN9D cells and midbrain dopaminergic neurons from MPP+-induced neurodegeneration. Neuromolecular Med. 14(4):317-27
Spittau B, Zhou X, Ming M, Krieglstein K
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(2012) TGFβ signalling plays an important role in IL4-induced alternative activation of microglia. J Neuroinflammation. 9:210
Zhou X, Spittau B, Krieglstein K
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(2013) ApoER2 and VLDLR are required for mediating reelin signalling pathway for normal migration and positioning of mesencephalic dopaminergic neurons. PLoS One. 16;8(8):e71091
Sharaf A, Bock HH, Spittau B, Bouché E, Krieglstein K
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(2013) Endogenous transforming growth factor-beta promotes quiescence of primary microglia in vitro. Glia. 61(2):287-300
Spittau B, Wullkopf L, Zhou X, Rilka J, Pfeifer D, Krieglstein K
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TGFβ1 inhibits IFNγ-mediated microglia activation and protects mDA neurons from IFNγ-driven neurotoxicity. (2015) J Neurochem. 134(1):125-34
Zhou X, Zöller T, Krieglstein K, Spittau B
