Class II HLH proteins heterodimerize with class I HLH/E proteins to regulate transcription. Here, we show that E proteins sharpen neurogenesis by adjusting the neurogenic strength of the distinct proneural proteins. We find that inhibiting BMP signaling or its target ID2 in the chick embryo spinal cord, impairs the neuronal production from progenitors expressing ATOH1/ASCL1, but less severely that from progenitors expressing NEUROG1/2/PTF1a. We show this context-dependent response to result from the differential modulation of proneural proteins’ activity by E proteins. E proteins synergize with proneural proteins when acting on CAGSTG motifs, thereby facilitating the activity of ASCL1/ATOH1 which preferentially bind to such motifs. Conversely, E proteins restrict the neurogenic strength of NEUROG1/2 by directly inhibiting their preferential binding to CADATG motifs. Since we find this mechanism to be conserved in corticogenesis, we propose this differential co-operation of E proteins with proneural proteins as a novel though general feature of their mechanism of action.The brain and spinal cord are made up of a range of cell types that carry out different roles within the central nervous system. Each type of neuron is uniquely specialized to do its job. Neurons are produced early during development, when they differentiate from a group of cells called neural progenitor cells. Within these groups, molecules called proneural proteins control which types of neurons will develop from the neural progenitor cells, and how many of them.Proneural proteins work by binding to specific patterns in the DNA, called E-boxes, with the help of E proteins. E proteins are typically understood to be passive partners, working with each different proneural protein indiscriminately. However, Le Dréau, Escalona et al. discovered that E proteins in fact have a much more active role to play.Using chick embryos, it was found that E proteins influence the way different proneural proteins bind to DNA. The E proteins have preferences for certain E-boxes in the DNA, just like proneural proteins do. The E proteins enhanced the activity of the proneural proteins that share their E-box preference, and reined in the activity of proneural proteins that prefer other E-boxes. As a result, the E proteins controlled the ability of these proteins to instruct neural progenitor cells to produce specific, specialized neurons, and thus ensured that the distinct types of neurons were produced in appropriate amounts.These findings will help shed light on the roles E proteins play in the development of the central nervous system, and the processes that control growth and lead to cell diversity. The results may also have applications in the field of regenerative medicine, as proneural proteins play an important role in cell reprogramming.
Le Dréau, G., Escalona, R., Fueyo, R., Herrera, A., Martínez, J. D., Usieto, S., … Marti, E. (2018). E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors’ activity in an E-box-dependent manner. ELife, 7. https://doi.org/10.7554/elife.37267