The Role of the Transcription Factor Bcl11a in Midbrain Dopaminergic Neurons

Marianna Tolve1, Ayse Ulusoy2, Alesja Dernst1, Gabriela O. Bodea1, Pentao Liu3, Walid Khaled4, Neal Copeland5, Heinz Beck6, Stephan Baader7, Donato Di Monte2, Sandra Blaess1

1 Neurodevelopmental Genetics, Institute of Reconstructive Neurobiology, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany
2 German Center for Neurodegenerative Diseases (DZNE), Bonn
3 The Wellcome Trust Sanger Institute, Cambridge, UK
4 Department of Pharmacology, Cambridge University, UK
5 Institute for Academic Medicine, Houston Methodist, USA
6 Laboratory of Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn
7 Institute of Anatomy, University of Bonn

Midbrain dopaminergic (mDA) neurons of the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) project to multiple forebrain target regions and modulate various behaviors. Transcription factor codes established during development may define the identity of specific mDA neuronal subsets and could ultimately contribute to the determination of their projection targets, their functional properties and their susceptibility to neurodegeneration. Bcl11a is a C2H2-like zinc finger transcription factor expressed in a subset of mDA neurons in the lateral VTA and the SNc. Using viral tracing experiments, we show that the olfactory tubercles are a major projection target of Bcl11a-expressing VTA-mDA neurons. To examine Bcl11a function in development and maintenance of mDA neurons, we inactivated Bcl11a specifically in mDA neurons during development (Bcl11a cko mice). We find that differentiation and maintenance of Bcl11a-positive mDA neurons is not obviously affected in Bcl11a cko mice. However, overexpression of alpha-synuclein in the SNc leads to a significantly greater reduction in the number of SNc-mDA neurons in Bcl11a cko animals as compared to controls. These results indicate that Bcl11a could play a neuroprotective role within SN-mDA neurons against alpha-synuclein-induced neurodegeneration.