Neuronal Differentiation and Maintenance

Our research is focussed on neurons located in the mammalian ventral midbrain and synthesizing the neurotransmitter dopamine (DA). These mesodiencephalic dopaminergic (mdDA) neurons comprise two nuclei, the substantia nigra pars compacta (SNc, A9 group) and ventral tegmental area (VTA, A10 group). The SNc DA neurons are part of the basal ganglia circuitry controlling voluntary movements and postural reflexes, as well as rule-based reinforcement learning. The VTA DA neurons, by contrast, are implicated in the control and modulation of cognitive, affective and motivational/rewarding behaviours.

The degeneration or dysfunction of the mdDA neurons in the human brain has devastating consequences for adult life: their loss leads to the motor symptoms of Parkinson’s Disease (PD), whereas a dysfunction of mdDA neurotransmission underlies 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 disorders 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.

Using the mouse is our preferred model system, 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 and neuroprotection of these cells throughout embryonic development and 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 red nucleus (RN) and oculomotor (OM) neurons, 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 as well as the direct reprogramming of somatic cells into mdDA neurons.

To understand the complex dynamics of these processes on a systems level, we have begun to model mathematically some of the genetic interactions taking place in the mid-/hindbrain region and during mdDA neuron development in close collaboration with the team Bioinformatics (IDG) and researchers at the Institute of Computational Biology (ICB), Helmholtz Zentrum München. For this purpose, we have also built up a public and highly curated database for detailed information about gene expression patterns and genetic interactions in the different regions of the developing mouse CNS that can be accessed at (http://mouseidgenes.helmholtz-muenchen.de)