BEN factors are conserved CSL co-repressors in Notch-mediated neural development. Our general goal is to understand how cell signaling pathways mediate accurate transcriptional gene control during development. We focus on the Notch signaling pathway and its roles in directing neural cell fates and states. We strive to elucidate general principles of gene regulation by combining studies in both Drosophila and mammalian model systems. This proposal describes first in vivo functional studies of BEN-solo domain proteins. From our Drosophila work, we found that the BEN-solo factor Insensitive (Insv). regulates Notch signaling and peripheral nervous system development by acting as a direct corepressor for the Notch transcription factor CSL. We will further study its genetic requirements, dissect its functional domains, and elucidate how it cooperates with other chromatin factors to induce transcriptional repression. We build upon this proprietary knowledge to study roles of mammalian BEN-solo factors during neural development, and we have preliminary data on their ability to inhibit Notch signaling and affect neural stem cell self-renewal and differentiation. These phenotype-driven studies will be complemented by genomewide analyses of chromatin binding of CSL and BEN-solo factors in flies and mice, from which we will extract Notch-regulated enhancers. We will validate enhancers in vivo with emphasis on neural regulatory elements. We hope to determine conserved features of N/CSL/BEN target networks in the nervous system. In addition, these data potentially shed light on CSL-independent association of BEN-solo proteins with chromatin, which we will address using functional assays. Overall, this proposal combines a variety of experimental approaches and model systems to investigate a novel conserved neural corepressor in the Notch pathway.

Public Health Relevance

Normal development requires cell-cell signaling and precise control over gene regulation. We study this with respect to the Notch pathway, a cell communication system that is fundamental to establishment of cell fates, tissue patterning, and gene control. Through our studies of fruitfly mechanosensory bristles, which require Notch signaling for their accurate development, we found that a BEN family protein regulates Notch signaling and bristle development. This factor associates with chromatin and binds the Notch transcription factor to oppose Notch signaling. Learning from these studies, we engaged first studies of related BEN proteins in the mammalian nervous system, and how they affect the self-renewal of neural stem cells in the embryo and adult. Finally, we are creating genomewide maps of the locations of the Notch transcription factor and BEN proteins. These data yield genetic, biochemical, and bioinformatic insights into the function of a novel conserved family of Notch regulators, and their roles in gene regulatory networks underlying neural development.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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Sloan-Kettering Institute for Cancer Research
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Kavaler, Joshua; Duan, Hong; Aradhya, Rajaguru et al. (2018) miRNA suppression of a Notch repressor directs non-neuronal fate in Drosophila mechanosensory organs. J Cell Biol 217:571-583
Duan, Hong; de Navas, Luis F; Hu, Fuqu et al. (2018) The mir-279/996 cluster represses receptor tyrosine kinase signaling to determine cell fates in the Drosophila eye. Development 145:
Yao, Liqun; Wang, Shenqiu; Westholm, Jakub O et al. (2017) Genome-wide identification of Grainy head targets in Drosophila reveals regulatory interactions with the POU domain transcription factor Vvl. Development 144:3145-3155
Kan, Lijuan; Grozhik, Anya V; Vedanayagam, Jeffrey et al. (2017) The m6A pathway facilitates sex determination in Drosophila. Nat Commun 8:15737
Garaulet, Daniel L; Sun, Kailiang; Li, Wanhe et al. (2016) miR-124 Regulates Diverse Aspects of Rhythmic Behavior in Drosophila. J Neurosci 36:3414-21
Sanfilippo, Piero; Smibert, Peter; Duan, Hong et al. (2016) Neural specificity of the RNA-binding protein Elav is achieved by post-transcriptional repression in non-neural tissues. Development 143:4474-4485
Garaulet, Daniel L; Lai, Eric C (2015) Hox miRNA regulation within the Drosophila Bithorax complex: Patterning behavior. Mech Dev 138 Pt 2:151-159
Sun, Kailiang; Jee, David; de Navas, Luis F et al. (2015) Multiple In Vivo Biological Processes Are Mediated by Functionally Redundant Activities of Drosophila mir-279 and mir-996. PLoS Genet 11:e1005245
Dai, Qi; Ren, Aiming; Westholm, Jakub O et al. (2015) Common and distinct DNA-binding and regulatory activities of the BEN-solo transcription factor family. Genes Dev 29:48-62
Shenker, Sol; Miura, Pedro; Sanfilippo, Piero et al. (2015) IsoSCM: improved and alternative 3' UTR annotation using multiple change-point inference. RNA 21:14-27

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