Foxn1 in Skin Development, Homeostasis and Wound Healing
Abstract
:1. Introduction
2. Foxn1 in Skin Development
2.1. Foxn1 over Evolution Time
2.2. Foxn1 in the Development of Skin Tissue and Skin Appendages
2.2.1. Foxn1 during Embryonic Development in Mice
2.2.2. Foxn1 during Postnatal Development
2.2.3. Foxn1 in Hair Follicle Morphogenesis
2.2.4. Foxn1 in Skin and Hair Pigmentation
2.2.5. Foxn1 Deficient (Nude) Mice
2.2.6. Foxn1 Deficient Human Nude/SCID Phenotype
2.2.7. Foxn1 Transgenic Animal Models
3. Foxn1 in Mature Skin Homeostasis
3.1. Foxn1 Localisation and Expression
3.2. The Role of Foxn1 in Epidermis: Proliferation, Differentiation and Apoptosis
3.3. Age Related Foxn1 Modulation
3.4. Foxn1 Regulation
3.5. Foxn1 and Dermal Compartment of the Skin
4. Foxn1 in Skin Wound Healing
4.1. Scar-Less Skin Wound Healing in Foxn1 Deficient (Nude) Mice
4.2. Foxn1 in Reparative (Scar-Forming) Skin Wound Healing
4.3. Foxn1 as a Transcriptional Switch between Scar-Free and Scar-Forming Skin Healing
4.4. Foxn1 among Transcription Factors and Signalling Pathways in the Skin Healing Process
5. Conclusions and Future Directions
Author Contributions:
Funding
Conflicts of Interest
References
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Characteristic of Foxn1 Deficiency | |
---|---|
Mouse (Nude) | Human (Nude/SCID) |
Mutations in the Foxn1 gene identified in the mouse allele nu, located on chromosomes 11; a single base-pair deletion in the Foxn1 coding sequence leads to a frame shift and premature termination in the DBD [22,67]; | Mutation in human FOXN1 gene recognised as a homozygous C-to-T transition (CGA to TGA) at nucleotide position 792 resulted in a nonsense mutation at residue 255 (R255X) in exon 5 [70]; |
The translated FOXN1, Foxn1, proteins are nonfunctional in human and mice, respectively and lead to similar defects [23,24,25]; Pleiotropic mutation categorised into two independent phenotypic responses: (i) impaired skin keratinisation and aberrant HFs development [13,19,23] and (ii) thymus dysgenesis that leads to T-cell deficiency [23,67]; | |
Mutants represent multiple skin defects [13,19]:
| Foetuses at 15th weeks show tight, shiny and smooth skin associated with a lack of thymus, anencephaly and spina bifida, indicating that beside its role in the thymus and skin epithelium, FOXN1 might also be involved in neurulation in humans [72]; Infant mutants demonstrate complete alopecia of the scalp, eyebrow, and eyelashes and nail dystrophy associated with a primary severe T-cell immunodeficiency [23,73]. |
Attributes to Foxn1 Activity in the Mice Skin | Attributes to Foxn1 Deficiency in the Mice Skin | |
---|---|---|
Development | Prenatal stage: Foxn1 expression detected on E13 in the developing nasal region; and by E15.5–16.5 Foxn1 occupied entire epidermis including developing HF of the fur coat [19]; 2065 genes differentially regulated (up and down) between skin from B6 embryo at E14 (model of skin regeneration) and E18 (model of skin reparation) [41]; Early neonatal stage: Foxn1 expression (postpartum days P1–P2) reported in the hair shaft and throughout the developing IRS and in a matrix compartment of hair bulb suggesting that Foxn1 correlates with the onset of terminal differentiation [19]; | Prenatal stage: Lack of Foxn1 activity at E16.5 (Foxn1 priming) keeps skin of nude mice in the immature stage resembling the phenomena of neoteny [41]; |
Homeostasis | Foxn1 expression in epithelial cells (epidermis) initiates terminal differentiation program and stimulates neighboring epithelial cell proliferation in paracrine manner [14,19,51]; Foxn1 participates in the development of skin epithelial cells coloration through activation of epithelial cells to emit signals (FGF-2) recognisable by melanocytes [54]; Epidermal Foxn1 expression impact the skin: (i) decreased levels of anti-fibrotic cytokine Tgfbeta3; (ii) cultured DF exhibited reduced adipogenic differentiation capacity [88]; | Impaired keratinisation of epidermis and hair shaft results in “hairless phenotype” [24,25]; Aberrant differentiation of epidermal keratinocytes manifests by inhibition of early differentiation markers (Krt1, -10), overproduction and accumulation of late differentiation markers (profilaggrin, loricrin, involucrin) and abnormal thickening of epidermis [13,14]; Increased amounts of cholesterol sulfate, phospholipids, sphingolipids and fatty acids in the skin when compare to the Foxn1 -active mouse models [89]; |
Wound healing | The process of healing occurs with fibrosis and scar formation, a condition characterised by excessive deposition of ECM protein rich in collagens [97,98,99]; Foxn1 acts as a key molecular player in re-epithelialisation and EMT processes in post-wounded skin tissues [16]. | Perfect healing in the process of regeneration characterised by lack of a scar, high levels of hyaluronic acid, low levels of collagen and pro-scarring cytokines (PDGF-B and TGF β1), and unique bimodal pattern of Mmp-9 and Mmp-13 expression [42,43]. |
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Bukowska, J.; Kopcewicz, M.; Walendzik, K.; Gawronska-Kozak, B. Foxn1 in Skin Development, Homeostasis and Wound Healing. Int. J. Mol. Sci. 2018, 19, 1956. https://doi.org/10.3390/ijms19071956
Bukowska J, Kopcewicz M, Walendzik K, Gawronska-Kozak B. Foxn1 in Skin Development, Homeostasis and Wound Healing. International Journal of Molecular Sciences. 2018; 19(7):1956. https://doi.org/10.3390/ijms19071956
Chicago/Turabian StyleBukowska, Joanna, Marta Kopcewicz, Katarzyna Walendzik, and Barbara Gawronska-Kozak. 2018. "Foxn1 in Skin Development, Homeostasis and Wound Healing" International Journal of Molecular Sciences 19, no. 7: 1956. https://doi.org/10.3390/ijms19071956