2015 Theses Doctoral

Regulatory Logic of Pan-neuronal Gene Expression in Caenorhabditis elegans

Stefanakis, Nikolaos

Nervous systems of all organisms are remarkably complex. This complexity is a reflection of the great diversity of the nervous systems’ basic units, the neurons. There is a large variety of different neuron types that differ in their morphology, function and their underlying molecular composition. Even though neurons are very diverse, they all share common features, namely cellular projections (axons and dendrites) and synapses. Genes expressed in the entire nervous system, called pan-neuronal genes, encode the molecular correlates to these common features. Although a lot is known about how specific transcription factors, Terminal Selectors (TS), specify the different neuronal types by co-regulating neuron type specific gene expression, much less is understood about the regulatory programs that control the expression of pan-neuronal genes. Addressing this question is key to understanding how neuronal fate is determined. In this thesis I have explored the regulatory logic of pan-neuronal genes in C. elegans. After performing an extensive analysis of the cis-regulatory regions of a set of pan-neuronal genes, defined in this study, I have found that the expression of these genes is regulated in a modular and redundant manner. Modular because for a given pan-neuronal gene there are different cis-regulatory elements controlling its expression in different sets of neurons; redundant because there are more than one transcription factors that can activate expression of a given pan-neuronal gene in the same neuron types. Interestingly I have found that Terminal Selectors can redundantly regulate pan-neuronal gene expression together with other transcription factors. I have also identified the HOX genes as one example of such factors that act redundantly with Terminal Selectors to directly regulate pan-neuronal gene expression in the C. elegans ventral nerve cord neurons. Neuronal gene expression regulatory programs therefore fall into two fundamentally distinct categories. Neuron type specific genes are generally controlled by discrete and non-redundantly acting regulatory inputs, while pan-neuronal gene expression is controlled by diverse, coincident and seemingly redundant regulatory inputs.