Molecular Regulation of Hair Follicle Stem and Progenitor Cell Homeostasis
Maintenance of adult stem cells and their progenitor cells is critical for proper homeostasis of their resident tissues. Defects in tissue stem or progenitor cell maintenance can cause developmental disorders, premature aging, and cancers. Identification of transcription factors regulating these processes have yielded significant insight regarding the mechanisms necessary for tissue homeostasis. The mouse hair follicle provides a dynamic system that is well suited for the study of tissue stem cell and progenitor cell regulation. Utilizing an inducible epithelial knockout system, I investigated the role of the transcription factor Gata6 in the hair follicle and discovered that Gata6 is essential for initiation and maintenance of hair follicle growth. This work found Gata6 in control of the renewal of rapidly proliferating hair progenitors and hence the extent of production of terminally differentiated lineages. In the absence of Gata6, progenitor cells in vivo as well as epidermal keratinocytes in culture accumulate DNA damage and are lost to apoptosis. Gata6 in the hair appears to protect progenitor cells from DNA damage associated with proliferation. This is accomplished, in part, through EDA-receptor signaling adaptor EDARADD and NF- kB pathway activation, known to be important for DNA-damage repair and stress response in general, and for hair follicle growth in particular. In cultured keratinocytes, Edaradd rescued DNA damage, cell survival and proliferation of Gata6 knockout cells. This Gata6-Edaradd-NF-kB pathway also activated the minichromosome maintenance factor Mcm10, which plays an important role in DNA replication processivity and DNA damage repair in response to replication stress. My data expands the role of Gata6, which has predominantly been recognized as a developmental factor for mesodermal and endodermal tissue lineages, to an ectodermal tissue where it plays a critical role in genome maintenance of progenitor cells. This work adds to other recent work in embryonic stem and neural progenitor cells, suggesting a model whereby developmentally regulated transcription factors protect from DNA damage associated with proliferation at key stages of rapid tissue growth. Our data may also provide a better understanding of why Gata6 is a frequent target of amplification in cancers and provide potential targets for treating Gata6 amplified cancers.
Hair Follicle; Stem Cell; Molecular biology
Lis, John T.; Schimenti, John C.
Biochemistry, Molecular and Cell Biology
Ph. D., Biochemistry, Molecular and Cell Biology
Doctor of Philosophy
dissertation or thesis