Abstract
ABSTRACTNeural bHLH transcription factors play a key role in the early steps of neuronal specification in many animals. We have previously observed that the Achaete-Scute HLH-3, the Olig HLH-16 and their binding partner the E-protein HLH-2 activate the terminal differentiation program of a specific class of cholinergic neurons, AIY, in Caenorhabditis elegans. Here we identify a role for a fourth bHLH, the Neurogenin NGN-1, in this process, raising the question of why so many neural bHLHs are required for a single neuronal specification event. Using quantitative imaging we show that the combined action of different bHLHs is needed to activate the correct level of expression of the terminal selector transcription factors TTX-3 and CEH-10 that subsequently initiate and maintain the expression of a large battery of terminal differentiation genes. Surprisingly, the different bHLHs have an antagonistic effect on another target, the proapoptotic BH3-only factor EGL-1, normally not expressed in AIY and otherwise detrimental for its specification. We propose that the use of multiple neural bHLHs allows robust neuronal specification while, at the same time, preventing spurious activation of deleterious genes.
Highlights
The combined action of several neural bHLHs ensures the robust activation of terminal selector transcription factor expression and prevents the activation of deleterious genes
By quantifying the initiation of the terminal selectors ttx-3 and ceh-10, using CRISPRengineered lines, we show that the three neural bHLH factors, NGN-1, HLH-3 and HLH-16 act together to set the correct level of terminal selector expression, ensuring robust, 100% efficient, neuronal specification
In an RNAi screen for bHLH factors affecting the AIY neuron, we identified a role for NGN-1, the only Neurogenin ortholog in C. elegans
Summary
This functional complexity is mirrored by the high diversity of neuronal cell types of their nervous system. The correct number of neurons of each neuronal cell type has to be produced so that the nervous system can function properly. How such a level of precision is reached in a robust manner remains poorly understood. Terminal selectors have to be activated in very precise sets of postmitotic neurons, at the right time and correct level. How this is achieved in a highly accurate manner is poorly characterized
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