Neuronal Differentiation and Maintenance
Our research is focussed on neurons located in two nuclei of the mammalian ventral midbrain, the substantia nigra pars compacta (SNc, A9 group) and ventral tegmental area (VTA, A10 group), synthesizing the neurotransmitter dopamine (DA). The degeneration of these mesodiencephalic dopaminergic (mdDA) neurons in the human brain leads to the cardinal motor symptoms of Parkinson’s Disease (PD), whereas a dysfunction of DA neurotransmission is thought to underlie the pathogenesis of severe psychiatric illnesses such as schizophrenia, addiction and depression. Up to date, preventive or curative therapies are not available for none of these disorders. However, more and more evidence is accumulating that the pathogenic process of these diseases starts already during prenatal or early postnatal development. Moreover, the prospect of stem-cell based regenerative therapies for PD has promoted the interest of developmental neurobiologists in deciphering the molecular cues and mechanisms controlling the generation of mdDA neurons in the mammalian brain.
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Using the mouse as our preferred in vivo model, we are aiming at dissecting the genetic networks and molecular signalling cascades underlying the establishment of the mdDA progenitor domain close to the mid-/hindbrain boundary (MHB), the commitment of these progenitors and their progeny to the mdDA cell fate, the proper differentiation of the mdDA precursors into mature mdDA neurons, and the survival of these cells throughout adulthood. In addition, we are studying the genetic cues and signalling pathways controlling the development of neuronal populations arising in close vicinity to the mdDA neurons, such as the glutamatergic projection neurons of the red nucleus (RN), the cholinergic motorneurons of the oculomotor (OM) nucleus, and GABAergic interneurons. We are complementing our in vivo analyses with cell culture-based paradigms and the in vitro differentiation of mouse embryonic stem (ES) and induced pluripotent stem (iPS) cells into these distinct types of neurons.
Funding:
Our research is funded by
Most important publications:
Fischer, T., Faus-Kessler, T., Welzl, G., Simeone, A., Wurst, W. and Prakash, N. (2011). Fgf15-mediated control of neurogenic and proneural gene expression regulates dorsal midbrain neurogenesis. Dev. Biol., 350: 496-510.
Di Salvio, M., Di Giovannantonio, L. G., Acampora, D., Prosperi, R., Omodei, D., Prakash, N., Wurst, W., and Simeone, A. (2010). Otx2 controls neuron subtype identity in the ventral tegmental area and antagonizes vulnerability to the Parkinsonian toxin MPTP by suppressing Dopamine transporter. Nat. Neurosci. 13: 1481-1488.
Wurst, W. and Prakash, N. (2009). Genetic control of meso-diencephalic dopaminergic neuron development in rodents. In: Dopamine Handbook. Eds: Iversen, L. et al. Oxford University Press, Oxford, UK. pp. 141-159.
Prakash, N., Puelles, E., Freude, K., Trümbach, D., Omodei, D., Di Salvio, M., Sussel, L., Ericson, J., Sander, M., Simeone, A. and Wurst, W. (2009). Nkx6-1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain. Development 136: 2545-2555.
Prakash, N., Brodski, C., Naserke, T., Puelles, E., Gogoi, R., Hall, A., Panhuysen, M., Echevarria, D., Sussel, L., Weisenhorn, D. M., Martinez, S., Arenas, E., Simeone, A. and Wurst, W. (2006). A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo. Development 133: 89-98.