Stem Cells and Nervous System Development

Programme Leader: Lia Panman

Summary of Research Interests

 

Dopaminergic neurons located in the ventral mesencephalon are a highly heterogeneous neuronal population controlling diverse processes such as motor actions, cognition, motivation, reward and emotions. Several diseases are caused by the dysfunction of a selective population of dopaminergic neurons. For example in Parkinson’s disease dopaminergic neurons of the substantia nigra selectively degenerate, while neurons of the ventral tegmental area remain relatively spared. In contrast, disorders like anxiety and depression are associated with the dysregulation of ventral tegmental area dopaminergic neurons. Most aspects of the molecular program controlling the general differentiation of dopaminergic neurons are well defined. However, the processes involved in the subtype specification are largely unknown. The focus of our research is on determining the mechanisms involved in the diversification of dopaminergic neurons and the functional characterization of the distinct subtypes. Understanding these processes will enable us to develop embryonic stem cell based model systems for different diseases by employing the transcriptional determinants involved in subtype specification. Furthermore, the outcomes of our research may contribute to the understanding of the etiology of diseases associated with the dopaminergic system.

 

Our research focuses on the following two areas:

1. Differential vulnerability of mesencephalic dopaminergic neurons to neurotoxicity.

In several neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease and Huntington only a selective population of neurons is affected. The reason for the selective loss of a distinct population of neurons upon neurotoxic insult in these diseases is currently unclear. It is planned to develop an embryonic stem cell model system that can be used to study the effect of neurotoxic insult on vulnerable neuronal cell populations directly. We have previously shown that forced expression of neuronal lineage specific transcription factors can direct the differentiation of mouse embryonic stem cells with high efficiency into desired neuronal lineages, like dopamine neurons and different classes of motor neurons. Using a similar approach different neuronal cell types will be generated that are highly vulnerable to neurotoxic stress, e.g. substantia nigra dopaminergic neurons. Determination of gene expression patterns by RNA sequencing of several neuronal classes implicated in neurodegenerative diseases will give important insights into the mechanisms behind the differential sensitivity.

NesE

Forced expression of neuronal cell type specific transcription like Lmx1a, Nkx2.2, Phox2b and Olig2 under control of the nestin enhancer (NesE) in ES cell derived neuronal progenitor cells results in highly enriched cultures of specific neuronal cell types. mDN: mesencephalic dopaminergic neuron, 5HTN: serotonergic neuron, vMN: visceral motoneuron, sMN: somatic motoneuron.

2. Regulation of dopamine neuron subtype specification.

The dopaminergic neurons can broadly be subdivided into three anatomically and functionally distinct regions, which form the substantia nigra (A9), ventral tegmental area (A10) and the retrorubal field (A8). Recent studies have shown that this subdivision is an oversimplification and the system is far more heterogeneous. We are interested in deciphering the molecular mechanisms underlying dopamine neuron subtype specification and characterizing the function of the distinct subtypes in further detail.

Selected Publications

Panman L*., Papathanou M., Laguna A., Oosterveen T., Volakakis N., Acampora D., Kurtsdotter I., Yoshitake T., Kehr J., Joodmardi E., Muhr J., Simeone A., Ericson J., Perlmann T*. (2014). Sox6 and Otx2 control the specification of  substantia nigra and ventral tegmental area dopamine neurons. Cell reports (in press). *Corresponding author.

Panman L*., Mong J*., Alekseenko Z., Kee N., StantonLW, EricsonJ. and Perlmann T. (2014). Transcription factor-induced lineage programming of noradrenaline and motor neurons from embryonic stem cells. Stem  Cells  32(3), 609-622 * Joint first author                                                                        

Panman L., Andersson E., Hedlund E., Kee N., Mong J., Uhde C., Deng Q., Alekseenko Z., Sandberg R., Stanton L.W., Ericson J., Perlmann T. (2011). Transcription factor-induced lineage selection of stem cell derived neural progenitor cells. Cell Stem Cell 8(6), 663-675.

Panman L., Perlmann T. (2011). Tracing lineages to uncover neuronal identity. BMC Biology 9, 51

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