Our long-term goal is to understand transcriptional control mechanisms that underlie development and homeostasis of epidermis and hair follicles. Clim/Nli/Ldb transcriptional co-activators were discovered based on their ability to bind to LIM domains of LIM homeodomain factors, thus conferring transcriptional activation by this class of DNA-binding proteins. One member of this family of co-activators, Clim-2, is highly expressed in keratinocytes where it interacts with the LIM only protein, LMO-4, which is expressed in an overlapping manner in epidermis and hair follicles. Blocking Clim action in mouse epidermis leads to hair loss, abnormal hair cycling, and, in older mice, propensity to epidermal wounding. We hypothesize that Clim-2 regulates hair follicles by interacting with DNA-binding proteins by using LMO-4 as an adapter molecule. We have identified one candidate DNA-binding protein in this pathway, a novel mammalian transcription factor homologous to Drosophila NTF-1, which, when mutated in flies leads to a cuticular phenotype.
The specific aims are: (1) to use a transgenic mouse model to understand how Clim co-activators regulate epidermal and hair homeostasis. Specifically, we plan to identify genes regulated by Clims and to elicit the relationship of Clim to signaling pathways known to regulate hair follicle morphogenesis; (2) to use biochemical approaches to test the hypothesis that the association of LMO-4 with mNTF-1 allows the recruitment of Clim-2 co-activators; and (3) to use transgenic mouse models and gene deletion technology to elucidate the epidermal function of the novel transcription factor, mNTF-1, which was cloned based on its ability to interact with LMO-4. These studies should give insight into normal epidermal biology and how disruption of normal transcriptional control mechanisms leads to diseases such as abnormal wound healing and skin cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR044882-10S1
Application #
7276523
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Baker, Carl
Project Start
1998-08-01
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
10
Fiscal Year
2006
Total Cost
$56,625
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Plikus, Maksim V; Andersen, Bogi (2018) Skin as a window to body-clock time. Proc Natl Acad Sci U S A 115:12095-12097
Klein, Rachel Herndon; Hu, William; Kashgari, Ghaidaa et al. (2017) Characterization of enhancers and the role of the transcription factor KLF7 in regulating corneal epithelial differentiation. J Biol Chem 292:18937-18950
Klein, Rachel Herndon; Stephens, Denise N; Ho, Hsiang et al. (2016) Cofactors of LIM Domains Associate with Estrogen Receptor ? to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function. J Biol Chem 291:13271-85
Spitler, Ryan; Ho, Hsiang; Norpetlian, Frederique et al. (2015) Combination of low level light therapy and nitrosyl-cobinamide accelerates wound healing. J Biomed Opt 20:051022
Gordon, William M; Zeller, Michael D; Klein, Rachel H et al. (2014) A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia. J Clin Invest 124:5205-18
Watanabe, Kazuhide; Biesinger, Jacob; Salmans, Michael L et al. (2014) Integrative ChIP-seq/microarray analysis identifies a CTNNB1 target signature enriched in intestinal stem cells and colon cancer. PLoS One 9:e92317
Salmans, Michael L; Yu, Zhengquan; Watanabe, Kazuhide et al. (2014) The co-factor of LIM domains (CLIM/LDB/NLI) maintains basal mammary epithelial stem cells and promotes breast tumorigenesis. PLoS Genet 10:e1004520
Peyrard-Janvid, Myriam; Leslie, Elizabeth J; Kousa, Youssef A et al. (2014) Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Am J Hum Genet 94:23-32
Watanabe, Kazuhide; Villarreal-Ponce, Alvaro; Sun, Peng et al. (2014) Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor. Dev Cell 29:59-74
Bhandari, A; Gordon, W; Dizon, D et al. (2013) The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1. Oncogene 32:1497-507

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