E proteins differentially co-operate with proneural bHLH transcription factors to sharpen neurogenesis

Basic HLH proteins heterodimerize with class I HLH/E-proteins to promote transcription. Here we show that E-proteins differentially co-operate with proneural bHLH transcription factors sharpening their neurogeneic activity. 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 define the mechanisms of this differential response as a dual co-operation of E-proteins with proneural proteins. E-proteins synergize with bHLH proteins when acting on CAGSTG motifs, thereby facilitating the neurogenic activity of ASCL1/ATOH1 which preferentially bind to such motifs. Conversely, E-proteins restrict the strong neurogenic potential 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 dual co-operation of E-proteins with bHLH proteins as a novel though general feature of their mechanism of action.