Skin epithelial stem cell fate maintenance and lineage determination
Cancer cells often manifest defects of differentiation and display many characteristics of stem cells. How the stem cell genes are normally regulated and
how they are reactivated in cancer are poorly understood. My lab’s interest is to understand the molecular mechanisms of self-renewal and differentiation of stem cells. We
use mammalian skin as the model. Because skin provides a large surface barrier against the environment, it has a large pool of stem cells that are regularly activated to
give rise to progeny to maintain skin homeostasis and to respond to wound healing. Wnt signaling plays an important role in many developmental processes including stem
cells self-newing pathway. The transcription factors Tcf3 and Tcf4, which bind to beta-catenin to activate Wnt target genes, also bind to corepressors and repress them.
Both Tcf3 and Tcf4 are expressed in skin stem cells and are turned off as cell fates are specified.
In our previous work we engineered an inducible transgenic mouse model and showed that inducing the expression of Tcf3 in skin cells where Tcf3 is already down
regulated induces an immediate change in gene expression in a pattern similarly found in embryonic and adult skin stem cells. Inducing Tcf3 expression prevents cells from
differentiating into different lineages. We also used a knockout mouse model and showed that both Tcf3 and Tcf4 are required for the survival and maintenance of skin
epithelial stem cells.
Our previous work shows that Tcf3 and Tcf4 play an essential role in maintaining the progenitor cell fate, and suggests that their down regulation could be an
important molecular switch that allows cell fate specification. The microarray data from our inducible and knockout mouse model provides us a network of genes whose
activation and repression could function to maintain the undifferentiated progenitor state or to trigger the differentiated state. We are currently studying how these
target genes of Tcf3 and Tcf4 function, using genetic tools and a combination of knockdown and induced expression in both in vitro differentiation assay and in vivo
cell/skin grafting assay. We propose to identify the in vivo Tcf3/4 associated factors and Tcf3/4 target genes using isolated cells at different stages of development. Our
goal is to understand how Tcf3/4’s interaction with other factors affects how they control their target genes.
We also aim to identify the factors that activate Tcf3 and Tcf4 expression in skin progenitor cells and silences its expression in committed cells using a combination
of candidate gene approach and high throughput screen. We are interested in how this network of genes are regulated and function and in aged stem cells, and how they are
dysregulated in different diseases including cancer.
We are interested in identifying the cells surrounding the hair follicle stem cells that support the environment where stem cells maintain its self-renewal ability.
We are testing various approaches to isolate these support cells. The isolation of these cells would allow us to study how the environment communicates with the stem cells
and affect the self-renewal capacity of stem cells.
Answering these questions will provide a deeper understanding of how stem cells maintain their multipotent status and control cell fate specification, and will be
important for both regenerative medicine and anti-cancer therapeutics.
Selected Publications
Nguyen H, Merrill BJ, Polak L, Nikolova M, Rendl M, Shaver TM, Pasolli HA, Fuchs E (2009) Tcf3 and Tcf4 are essential for long-term homeostasis of skin epithelia.
Nature Genetics, in press. (Epub ahead of print)
Nguyen H, Rendl M, Fuchs E (2006) Tcf3 governs stem cell features and represses cell fate determination in skin. Cell 127:171-183.
Liu Y, Hedvat CV, Mao S, Zhu XH, Yao J, Nguyen H, Koff A, Nimer SD (2006) The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the
protein-ubiquitin ligase SCFSkp2. Molecular and Cellular Biology 26:3114-3123.
Zhu XH, Nguyen H, Halicka HD, Traganos F, Koff A (2004) Noncatalytic requirement for cyclin A-cdk2 in p27 turnover. Molecular and Cellular Biology
24:6058-6066.
Nguyen H, Gitig DM, Koff A (1999) Cell-free degradation of p27kip1, a G1 cyclin-dependent kinase inhibitor, is dependent on CDK2 activity and the proteasome.
Molecular and Cellular Biology 19:1190-1201.
Millard SS, Yan JS, Nguyen H, Pagano M, Kiyokawa H, Koff A (1997) Enhanced ribosomal association of p27Kip1 mRNA is a mechanism contributing to accumulation during
growth arrest. Journal of Biological Chemistry 272:7093-7098.
Contact Information
- Hoang Nguyen, Ph.D.
- Department of Molecular and Cellular Biology
- Center for Cell and Gene Therapy
- Baylor College of Medicine
- One Baylor Plaza N1120
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-1236
- Fax: (713) 798-1230
- E-mail: hoangn@bcm.edu
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