Establishing neuronal diversity in the dopaminergic system: the role of the transcription factor Bcl11a

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Midbrain dopaminergic neurons (MbDN) modulate movement, reward behavior and cognitive processes. Degeneration or dysfunction of MbDN is implicated in several common human disorders including Parkinson disease, depression and schizophrenia. How MbDNs, which constitute a relatively small neuronal population in the brain, can contribute to such diverse functions is still not fully understood. Recent evidence indicates that MbDN subtypes can be defined based on their molecular or neurochemical profile in the postnatal brain. In addition, it has been shown that anatomically and physiologically discrete MbDNs mediate distinct aspects of behavior. It remains unclear how this diversity of MbDNs is established during development and how a particular molecular identity is linked to the functional identity of an MbDN subtype. We hypothesize that transcription factor codes that are established in MbDN subsets during development define the identity of these specific MbDN subsets by determining their molecular make-up, their connectivity and their functional properties. By comparing gene expression profiles of two distinct MbDN subgroups during embryonic development, we have identified a number of transcription factors, which are expressed in subsets of MbDNs in the developing and adult brain. We propose to study how one of the identified factors, the Krüppel-like zinc finger transcription factor Bcl11a, determines the functional identity of an MbDN subpopulation. We will characterize the projections, physiology and function of the Bcl11a-expressing MbDN subtypes by combining genetic lineage analysis, optogenetic approaches and viral tracing methods. Moreover, we will generate a conditional knock-out mouse model to inactivate Bcl11a specifically in MbDN and analyze the consequences of the inactivation on MbDN fate and survival and on the behavior of the conditional knock-out mice. Our analysis will provide insight into how the developmentally determined molecular cell identity of MbDN subclasses determines their connectivity and function in the adult brain.