Abstract
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.
Highlights
The correct functioning of the vertebrate central nervous system (CNS) relies on the activity of a large variety of neurons that can be distinguished by their morphologies, physiological characteristics and anatomical locations (Zeng and Sanes, 2017)
These results revealed a correlation whereby the requirement of the canonical Bone morphogenetic proteins (BMPs) pathway for the generation of discrete spinal neuron subtypes is linked to the proneural protein expressed in the corresponding progenitor domain (Figure 1B,C)
The V2a/b interneurons that display intermediate sensitivity to BMP7/SMAD1/5 inhibition are derived from p2 progenitors that express both ASCL1 and NEUROG1 (Misra et al, 2014), while the relatively insensitive dI4 interneurons are derived from dP4 progenitors that express PTF1a together with low levels of ASCL1 (Figure 1B,C, Glasgow et al 2005)
Summary
The correct functioning of the vertebrate central nervous system (CNS) relies on the activity of a large variety of neurons that can be distinguished by their morphologies, physiological characteristics and anatomical locations (Zeng and Sanes, 2017). Neuronal differentiation and subtype specification are brought together by a small group of transcription factors (TFs) encoded by homologues of the Drosophila gene families Atonal, AchaeteScute, Neurogenins/dTap and p48/Ptf1a/Fer (Bertrand et al, 2002; Huang et al, 2014) These TFs represent a subgroup of the class II of helix-loop-helix proteins and all share a typical basic helixloop-helix (bHLH) structural motif, where the basic domain mediates direct DNA binding to CANNTG sequences (known as E-boxes) and the HLH region is responsible for dimerization and protein-protein interactions (Massari and Murre, 2000; Bertrand et al, 2002). They are typically referred to as proneural proteins, since they are both necessary and sufficient to switch on the genetic programs that drive
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