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E Proteins Sharpen Neurogenesis by Modulating Proneural Bhlh

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E Proteins Sharpen Neurogenesis by Modulating Proneural Bhlh RESEARCH ARTICLE E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors’ activity in an E-box-dependent manner Gwenvael Le Dre´ au1†*, Rene´ Escalona1†‡, Raquel Fueyo2, Antonio Herrera1, Juan D Martı´nez1, Susana Usieto1, Anghara Menendez3, Sebastian Pons3, Marian A Martinez-Balbas2, Elisa Marti1 1Department of Developmental Biology, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain; 2Department of Molecular Genomics, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain; 3Department of Cell Biology, Instituto de Biologı´a Molecular de Barcelona, Barcelona, Spain 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 *For correspondence: the chick embryo spinal cord, impairs the neuronal production from progenitors expressing [email protected] 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’ †These authors contributed activity by E proteins. E proteins synergize with proneural proteins when acting on CAGSTG motifs, equally to this work thereby facilitating the activity of ASCL1/ATOH1 which preferentially bind to such motifs. Present address: Conversely, E proteins restrict the neurogenic strength of NEUROG1/2 by directly inhibiting their ‡ Departamento de Embriologı´a, preferential binding to CADATG motifs. Since we find this mechanism to be conserved in Facultad de Medicina, corticogenesis, we propose this differential co-operation of E proteins with proneural proteins as a Universidad Nacional Auto´noma novel though general feature of their mechanism of action. de Me´xico, Me´xico City, Mexico DOI: https://doi.org/10.7554/eLife.37267.001 Competing interests: The authors declare that no competing interests exist. Funding: See page 25 Introduction Received: 05 April 2018 The correct functioning of the vertebrate central nervous system (CNS) relies on the activity of a Accepted: 09 August 2018 large variety of neurons that can be distinguished by their morphologies, physiological characteris- Published: 10 August 2018 tics and anatomical locations (Zeng and Sanes, 2017). Such heterogeneity is generated during the phase of neurogenesis, once neural progenitors have been regionally specified and are instructed to Reviewing editor: Jeremy exit the cell cycle and differentiate into discrete neuronal subtypes (Guillemot, 2007). Nathans, Johns Hopkins Neuronal differentiation and subtype specification are brought together by a small group of tran- University School of Medicine, United States scription factors (TFs) encoded by homologues of the Drosophila gene families Atonal, Achaete- Scute, Neurogenins/dTap and p48/Ptf1a/Fer2 (Bertrand et al., 2002; Huang et al., 2014). These Copyright Le Dre´au et al. This TFs represent a subgroup of the class II of helix-loop-helix proteins and all share a typical basic helix- article is distributed under the loop-helix (bHLH) structural motif, where the basic domain mediates direct DNA binding to terms of the Creative Commons Attribution License, which CANNTG sequences (known as E-boxes) and the HLH region is responsible for dimerization and pro- permits unrestricted use and tein-protein interactions (Massari and Murre, 2000; Bertrand et al., 2002). They are generally redistribution provided that the expressed in mutually exclusive populations of neural progenitors along the rostral-caudal and dor- original author and source are sal-ventral axes (Gowan et al., 2001; Lai et al., 2016). They are typically referred to as proneural credited. proteins, since they are both necessary and sufficient to switch on the genetic programs that drive Le Dre´au et al. eLife 2018;7:e37267. DOI: https://doi.org/10.7554/eLife.37267 1 of 29 Research article Developmental Biology eLife digest 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 Dre´au, 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. DOI: https://doi.org/10.7554/eLife.37267.002 pan-neuronal differentiation and neuronal subtype specification during development (Guille- mot, 2007). This unique characteristic is also illustrated by their ability to reprogram distinct neural and non-neural cell types into functional neurons (Masserdotti et al., 2016). Regulating the activity of these proneural proteins is crucial to ensure the production of appropri- ate numbers of neurons without prematurely depleting the pools of neural progenitors. In cycling neural progenitors, the transcriptional repressors HES1 and HES5 act in response to Notch signalling to maintain proneural TF transcripts oscillating at low levels (Imayoshi and Kageyama, 2014). The proneural proteins are also regulated at the post-translational level. Ubiquitination and phosphoryla- tion have been reported to control their stability, modify their DNA binding capacity or even termi- nate their transcriptional activity (Ali et al., 2011; Li et al., 2012; Ali et al., 2014; Quan et al., 2016). Furthermore, the activity of these proneural proteins is highly dependent on protein–protein interactions, and particularly on their dimerization status. It is generally admitted that these TFs must form heterodimers with the more broadly expressed class I HLH/E proteins to produce their tran- scriptional activity (Wang and Baker, 2015). In this way, the activity of proneural proteins can be controlled by upstream signals that regulate the relative availability of E proteins. Members of the Inhibitor of DNA binding (ID) family represent such regulators. As they lack the basic domain required for direct DNA-binding, ID proteins sequester E proteins through a physical interaction and thereby produce a dominant-negative effect on proneural proteins (Massari and Murre, 2000; Wang and Baker, 2015). Hence, several sophisticated regulatory mechanisms are available during development to control proneural protein activity and fine-tune neurogenesis. Bone morphogenetic proteins (BMPs) contribute to multiple processes during the formation of the vertebrate CNS (Liu and Niswander, 2005; Le Dre´au and Martı´, 2013). Yet it is only in the past few years that their specific role in controlling vertebrate neurogenesis has begun to be defined (Le Dre´au et al., 2012; Segklia et al., 2012; Choe et al., 2013; Le Dre´au et al., 2014). During spi- nal cord development, SMAD1 and SMAD5, two canonical TFs of the BMP pathway (Massague´ et al., 2005), dictate the mode of division that spinal progenitors adopt during primary neurogenesis. Accordingly, strong SMAD1/5 activity promotes progenitor maintenance while weaker activity enables neurogenic divisions to occur (Le Dre´au et al., 2014). This model explains how inhi- bition of BMP7 or SMAD1/5 activity provokes premature neuronal differentiation and the concomi- tant depletion of progenitors. However, it does not explain why the generation of distinct subtypes Le Dre´au et al. eLife 2018;7:e37267. DOI: https://doi.org/10.7554/eLife.37267 2 of 29 Research article Developmental Biology of dorsal interneurons are affected differently (Le Dre´au et al., 2012), nor how BMP signaling affects the activity of the proneural proteins expressed in the corresponding progenitor domains. Here, we have investigated these questions, extending our analysis to primary spinal neurogene- sis along the whole dorsal-ventral axis. As such, we identified a striking correlation between the requirement of canonical BMP activity for the generation of a particular neuronal subtype and the proneural protein expressed in the corresponding progenitor domain. Inhibiting the activity of BMP7, SMAD1/5 or their downstream effector ID2 strongly impaired the production of neurons
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