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Identification of two keratinocyte stem cell regulatory loci implicated in skin carcinogenesis
Natalia V Popova1, Kimberly A Teti, Kai Q Wu
1Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA. nvp2002@columbia.edu
Abstract:
Several converging lines of evidence suggest that keratinocyte stem cells including those clonogenic in vitro, are the target cells in skin carcinogenesis. However, the mechanism of their involvement in carcinogenesis continues to be unknown. Recently, we have demonstrated that the number of keratinocyte clonogenic stem cells from mice is a genetically defined and quantitative complex trait. In this study, we analyzed the size of the colonies in BALB/c, C57BL/6, and their (BALB/cxC57BL/6)F1 hybrid mice. We found that the size of the colonies is also genetically regulated and that there are at least two types of clonogenic keratinocytes that form either small or large colonies. Small and large colony numbers were significantly different in BALB/c and C57BL/6 mice. We performed a genome-wide scan of small and large colony number in the two backcrosses [BALB/cx (BALB/cxC57BL/6)F1]; [C57BL/6x (BALB/cxC57BL/6) F1]; and [(BALB/cxC57BL/6)F1x (BALB/cxC57BL/6)F1] intercross mice. We report here that the loci on chromosomes 4 and 9 play a role in the regulation of large and small colony number respectively. We conclude that mouse epidermis has two major types of stem cells generating small and large colonies, and regulated by different genes. Our results suggest that the loci, including one major and several minor loci linked to the subpopulation of keratinocytes forming small colonies were related, if not identical to, the loci linked to susceptibility or resistance to skin tumor promotion and skin tumor development.
Insights
Skin carcinogenesis involves keratinocyte stem cells. This study identifies two distinct stem cell types forming small and large colonies, regulated by genes on chromosomes 4 and 9, impacting skin tumor development.
Area of Science:
- Dermatology and Cancer Biology
- Stem Cell Biology
- Genetics and Genomics
Background:
- Keratinocyte stem cells are implicated as targets in skin carcinogenesis.
- The precise mechanisms of their involvement remain largely unknown.
- Previous work established keratinocyte stem cell number as a genetically influenced trait.
Purpose of the Study:
- To investigate the genetic regulation of clonogenic keratinocyte colony size.
- To identify genetic loci controlling the formation of small and large colonies.
- To explore the relationship between these loci and skin tumor susceptibility.
Main Methods:
- Analysis of colony size in BALB/c, C57BL/6, and (BALB/cxC57BL/6)F1 hybrid mice.
- Genome-wide scans utilizing backcross and intercross mouse models.
- Quantitative trait locus (QTL) mapping to identify regulatory genes.
Main Results:
- Colony size in clonogenic keratinocytes is genetically regulated.
- Two distinct populations of keratinocytes form small and large colonies, with differential numbers in BALB/c and C57BL/6 mice.
- Genetic loci on chromosomes 4 and 9 were identified as regulators of large and small colony numbers, respectively.
Conclusions:
- Mouse epidermis harbors at least two types of stem cells, generating small and large colonies, each under distinct genetic control.
- Genes regulating small colony formation are linked to susceptibility/resistance in skin tumor promotion and development.
- This provides a genetic basis for understanding stem cell heterogeneity in skin carcinogenesis.