"Funding from The Sontag Foundation will extend my research program into previously unexplored areas of astrocyte lineage development and expand the interface between neurodevelopment and tumor biology that exists within my laboratory. It is a privilege to be a member of this premier group of biologists, each focused on curing brain cancer using innovative and diverse approaches."
- Dr. Ben Deneen
About DSA-Funded Research
During embryogenesis stem cells go through a series of developmental steps that culminate in the generation of a cell that performs a set physiological task. In the developing central nervous system (CNS) these developmental steps include specification of lineage identity, migration, and terminal differentiation. While much attention has been paid to understanding the individual steps of development, our knowledge of how these steps are coordinated remains rudimentary. Thus the overarching goal of this proposal is to elucidate how the processes that control these steps during astro-glial development are linked.
Recently we identified Nuclear Factor I-A (NFIA) as a key transcription factor controlling the specification of glial cell identity in stem cells. In addition, NFIA promotes the migration of astrocyte precursors (ASPs) indicating that it coordinates the specification and migration steps of glial lineage development. To resolve how NFIA promotes ASP migration, we sought to identify its target genes and identified Daam2 as a candidate target. Daam2 is a member of the Daam-family of scaffolding proteins and its role during CNS development is uncharacterized. Our preliminary studies suggest that NFIA regulates Daam2 expression and that Daam2 can promote ASP migration. The studies outlined in this proposal will link glial specification to ASP migration, by examining the regulation and function of Daam2.
The processes that control cell migration are intimately associated with malignant tumor invasion. Given the highly invasive nature of glioblastoma multiforme (GBM), delineating the molecular processes that control normal ASP migration will reveal novel insight into GBM biology and treatment.
"Ben was among the most mature and focused, as well as productive, postdoc that I have ever had the privilege of working with in my lab. In my 23 years at Caltech, I have not seen such a demonstration of teamwork and collaboration, as I did during Ben's time in the lab."
David J. Anderson, Ph.D.
California Institute of Technology
Howard Hughes Medical Institute
"Dr. Deneen is emerging as one of the most talented young investigators in the field of gliogenesis, and he is poised to make important contributions."
David Rowitch, M.D., Ph.D.
University of California, San Francisco
Howard Hughes Medical Institute
- Glasgow S, Laug D, Brawley V, Zhang Z, Corder A, Yin Z , Wong STC, Li XN, Foster AE, Ahmed A, and Deneen B. (2013) The miR223-NFIA Axis Regulates Glial Precursor Proliferation and Tumorigenesis in the CNS. Journal of Neuroscience 33(33):13560-13568. PMID: 23946414 **Featured in Science “Editors Choice” http://www.sciencemag.org/content/341/6150/1044.4.short
- Glasgow S, Zhu W, Stolt CC, Huang TW, Chen F, LoTurco JJ, Neul JL, Wegner M, Mohila CM, and Deneen B. (2014) Mutual Antagonism Between Sox10 and NFIA Regulates Diversification of Glial Lineages and Glioma Sub-Types. Nature Neuroscience 17(10): 1322-1329. PMID:25151262
- Lee HK, Chaboub LS, Zhu W, Zollinger D, Rasband MN, Fancy SF, and Deneen B. (2015) Daam2-PIP5K is a novel regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron 85(6): 1227-1243. PMID: 25754822 **Highlighted in Faculty of 1000
- Chaboub LS, Manalo JM, Lee HK, Glasgow SM, Chen F, Kawasaki Y, Akiyama T, Kuo CT, Creighton CJ, Mohila CA, and Deneen B (2016) Temporal Profiling of Astrocyte Precursors Reveals Parallel Roles for Asef during Development and After Injury. Journal of Neuroscience (in revision).
- Glasgow SM, Carlson J, Kanfg P, Chaboub LS, Lee HK, Clovis Y, McEvilley RJ, Rosenfeld MG, Creighton CJ, Lee SK, Mohila CA, and Deneen B. (2016) Lineage specific chromatin architecture governs NFIA expression and glioma tumorigenesis. Nature Neuroscience (in revision).
- Lin CC, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J, Weston MC, Chen F, Mohila CA, Ahmed A, Patel AJ, Arenkiel BR, Noebels JL, Creighton CJ, and Deneen B. (2016) Identification of Diverse Astrocyte Populations and their Malignant Analogs. Nature Neuroscience (in revision).