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Forkhead box protein C1 (Forkhead-related protein FKHL7) (Forkhead-related transcription factor 3) (FREAC-3) [FKHL7] [FREAC3]


Identification of key genes and transcription factors in aging mesenchymal stem cells by DNA microarray data.

Mesenchymal stem cells (MSCs) are multipotent cells that can be widely used in stem cell therapy. However, few studies have revealed the potential mechanisms of the changes in aging MSC. In this study, microarray data GSE35955 was downloaded from the Gene Expression Omnibus database. Then limma package in R was used to filtrate differentially expressed genes (DEGs), Transcription factors (TFs) were predicted by DCGL package. After predicting TFs, protein-protein interaction (PPI) network and TF-mediated transcriptional regulation network were constructed. The functional and pathway enrichment analysis of screened DEGs, hub genes and TFs were conducted by the DAVID. Totally 156 up-regulated DEGs and 343 down-regulated DEGs were obtained. 6 hub genes (CTNNB1, PPP2R1A, FYN, MAPK1, PIK3C2A and EP300) were obtained from PPI network. 11 TFs (CREB1, [[CUX1]], EGR1, EP300, FOXC1, HSF2, MEF2A, PLAU, SP1, STAT1 and USF1) for DEGs were predicted and 2 highly scored co-expression relationships (EP300-PPP2R1A and STAT1-FOXC1) were acquired from the TF-mediated transcriptional regulation network. The discovery of the hub genes, TFs and pathways might contribute to the understanding of genetic and molecular functions of aging-related changes in MSC. Further validation studies on genes and TFs such as CTNNB1, FYN, PPP2R1A, MAPK1, EP300 and related biological processes and pathways, including adherens junction, DNA damage caused from oxidative stress, attribution of telomere, MSC differentiation and epigenetic regulation, are urgent for clinical prevention and treatment.

MeSH Terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Mesenchymal Stem Cells
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1
  • Oligonucleotide Array Sequence Analysis
  • Protein Interaction Maps
  • Protein Phosphatase 2
  • Proto-Oncogene Proteins c-fyn
  • Transcription Factors
  • beta Catenin


  • Differentially expressed genes
  • Enrichment analysis
  • Gene Expression Omnibus
  • Hub genes
  • Microarray analysis
  • Protein-protein interaction network
  • Transcriptional regulatory network

FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential.

Adult tissue stem cells (SCs) reside in niches, which orchestrate SC behavior. SCs are typically used sparingly and exist in quiescence unless activated for tissue growth. Whether parsimonious SC use is essential to conserve long-term tissue-regenerating potential during normal homeostasis remains poorly understood. Here, we examine this issue by conditionally ablating a key transcription factor Forkhead box C1 (FOXC1) expressed in hair follicle SCs (HFSCs). FOXC1-deficient HFSCs spend less time in quiescence, leading to markedly shortened resting periods between hair cycles. The enhanced hair cycling accelerates HFSC expenditure, and impacts hair regeneration in aging mice. Interestingly, although FOXC1-deficient HFs can still form a new bulge that houses HFSCs for the next hair cycle, the older bulge is left unanchored. As the new hair emerges, the entire old bulge, including its reserve HFSCs and SC-inhibitory inner cell layer, is lost. We trace this mechanism first, to a marked increase in cell cycle-associated transcripts upon Foxc1 ablation, and second, to a downstream reduction in E-cadherin-mediated inter-SC adhesion. Finally, we show that when the old bulge is lost with each hair cycle, overall levels of SC-inhibitory factors are reduced, further lowering the threshold for HFSC activity. Taken together, our findings suggest that HFSCs have restricted potential in vivo, which they conserve by coupling quiescence to adhesion-mediated niche maintenance, thereby achieving long-term tissue homeostasis.

MeSH Terms

  • Adult Stem Cells
  • Aging
  • Animals
  • Cadherins
  • Cell Adhesion
  • Cell Proliferation
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Hair Follicle
  • Mice, Knockout
  • Mice, Mutant Strains
  • Regeneration
  • Stem Cell Niche


  • FOXC1
  • aging
  • hair follicle
  • quiescence
  • stem cells

Foxf2: a novel locus for anterior segment dysgenesis adjacent to the Foxc1 gene.

Anterior segment dysgenesis (ASD) is characterised by an abnormal migration of neural crest cells or an aberrant differentiation of the mesenchymal cells during the formation of the eye's anterior segment. These abnormalities result in multiple tissue defects affecting the iris, cornea and drainage structures of the iridocorneal angle including the ciliary body, trabecular meshwork and Schlemm's canal. In some cases, abnormal ASD development leads to glaucoma, which is usually associated with increased intraocular pressure. Haploinsufficiency through mutation or chromosomal deletion of the human FOXC1 transcription factor gene or duplications of the 6p25 region is associated with a spectrum of ocular abnormalities including ASD. However, mapping data and phenotype analysis of human deletions suggests that an additional locus for this condition may be present in the same chromosomal region as FOXC1. DHPLC screening of ENU mutagenised mouse archival tissue revealed five novel mouse Foxf2 mutations. Re-derivation of one of these (the Foxf2(W174R) mouse lineage) resulted in heterozygote mice that exhibited thinning of the iris stroma, hyperplasia of the trabecular meshwork, small or absent Schlemm's canal and a reduction in the iridocorneal angle. Homozygous E18.5 mice showed absence of ciliary body projections, demonstrating a critical role for Foxf2 in the developing eye. These data provide evidence that the Foxf2 gene, separated from Foxc1 by less than 70 kb of genomic sequence (250 kb in human DNA), may explain human abnormalities in some cases of ASD where FOXC1 has been excluded genetically.

MeSH Terms

  • Aging
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Biological Specimen Banks
  • Cornea
  • DNA
  • Embryo, Mammalian
  • Ethylnitrosourea
  • Eye Abnormalities
  • Forkhead Transcription Factors
  • Genetic Loci
  • Homozygote
  • Iris
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Phylogeny