MRC National Institute for Medical Research, London
Science for Health
Siew-Lan Ang group project:
Identifying gene networks regulating mDA progenitor specification and differentiation
Midbrain dopaminergic (mDA neurons) are generated from floor plate progenitors from the caudal diencephalon and the midbrain. During neurogenesis, these progenitors differentiate and migrate in a precise manner to form a pattern characteristic of mdA neurons with rostral-caudal differences.
We are interested in identifying the gene regulatory networks that lead to the differentiation of mDA neurons from neural stem cells. Recent progress in this area has identified some of the major transcription factors (TFs) that regulate mDA progenitor specification and differentiation during mouse embryonic development. These include the forkhead/winged helix TF Foxa1 and Foxa2, the LIM homeodomain TFs Lmx1a and Lmx1b and the homeodomain TF Otx2. Our current understanding is that a single factor alone is not sufficient, but rather a combination of TFs interact to convert a neural progenitor into an mDA progenitor and to promote its differentiation into mDA neurons. How these TFs interact and the molecular targets downstream that regulate proliferation, neuronal differentiation, cell migration and axon targeting of mDA cells remain to be determined.
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Adult midbrain TH+ dopaminergic neurons in the nuclei of the substantia nigra pars compacta (SN) and ventral tegmental area (VTA) maintain expression of Foxa2 protein
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Genetic fate mapping show that progenitors in the medial floor plate region generate midbrain dopaminergic neurons (arrows) in several nuclei including the VTA, SN and interfascicular nucleus (IFN).
Our approach is to identify the role of each transcription factor to the development of mDA cells by determining its direct transcriptional targets at the genome wide level using chromatin immunoprecipitation followed by high-throughput sequencing. In addition, we are also studying the different cellular processes regulated by these TFs during mDA neuron development by genetic studies in mice using the Cre-loxP system. By combining the functional studies with the molecular gene regulatory networks, we aim to discover novel genetic and cellular mechanisms that regulate differentiation of mDA neurons into functional neuronal circuits.
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Dopaminergic progenitors expressing Lmx1a+ in the ventral midbrain of mouse embryos at E12.5 (left) or generated by in vitro differentiation of mouse embryonic stem cells (right)
Ang group
Recent publications
Research projects
- Identifying gene networks regulating mDA progenitor specification and differentiation
- Development of POMC and NPY neurons in the arcuate nucleus
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