Talk:Integumentary System Development

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Cite this page: Hill, M.A. (2021, November 26) Embryology Integumentary System Development. Retrieved from

10 Most Recent Papers

Note - This sub-heading shows an automated computer PubMed search using the listed sub-heading term. References appear in this list based upon the date of the actual page viewing. Therefore the list of references do not reflect any editorial selection of material based on content or relevance. In comparison, references listed on the content page and discussion page (under the publication year sub-headings) do include editorial selection based upon relevance and availability. (More? Pubmed Most Recent)

Integument Development

<pubmed limit=5>Integument Development</pubmed>


Characterization of mesenchymal cells beneath cornification of the fetal epithelium and epidermis at the face: an immunohistochemical study using human fetal specimens

Anat Cell Biol. 2016 Mar;49(1):50-60. doi: 10.5115/acb.2016.49.1.50. Epub 2016 Mar 28.

Kim JH1, Jin ZW2, Murakami G3, Cho BH4.


Fetal development of the face involves a specific type of cornification in which keratinocytes provide a mass or plug to fill a cavity. The epithelial-mesenchymal interaction was likely to be different from that in the usual skin. We examined expression of intermediate filaments and other mesenchymal markers beneath cornification in the fetal face. Using sections from 5 mid-term human fetuses at 14-16 weeks, immunohistochemistry was conducted for cytokeratins (CK), vimentin, nestin, glial fibrilary acidic protein, desmin, CD34, CD68 and proliferating cell nuclear antigen (PCNA). Fetal zygomatic skin was composed of a thin stratum corneum and a stratum basale (CK5/6+, CK14+, and CK19+) and, as the intermediate layer, 2-3 layered large keratinocytes with nucleus. The basal layer was lined by mono-layered mesenchymal cells (CD34+ and nestin+). Some of basal cells were PCNA-positive. In the keratinocyte plug at the external ear and nose, most cell nuclei expressed PCNA, CK5/6, CK14, and CK19. Vimentin-positive mesenchymal cells migrated into the plug. The PCNA-positive nucleus as well as mesenchymal cell migration was not seen in the lip margin in spite of the thick keratinocyte layer. The lingual epithelium were characterized by the CK7-positive stratum corneum as well as the thick mesenchymal papilla. CD68-positive macrophages were absent in the epidermis/epithelium. Being different from usual cornification of the skin, loss of a mesenchymal monolayer as well as superficial migration of mesenchymal cells might connect with a specific differentiation of keratinocyte to provide a plug at the fetal nose and ear. KEYWORDS: Cornification; Epidermis; Epithelium; Human fetuses; Keratinocytes PMID: 27051567 PMCID: PMC4819077 DOI: 10.5115/acb.2016.49.1.50

Chapter IX: Skin and Integument - Evolution of Skin

Key words: Skin evolution, colour, hairlessness, vitamin D production, integumentary specializations, diseases and infections of the skin,

  1. Evolving the largest organ of the body
    1. Mammals the defining feature
    2. The barrier between humans and their environment
    3. The sensory function
    4. The immune function
    5. The role of the environment in skin evolution
    6. Social changes with clothing
  2. Developmental embryology of the skin
    1. The germ layers - ectoderm, mesoderm and endoderm
    2. Embryological changes of the skin
    3. Evolving the human vernix caseosa
      1. Evolving survival in the uterine environment
      2. The vernix structure and function
    4. Postnatal changes in the skin
      1. Cornification, the specialized death in skin
      2. Pattern formation in skin, fingerprints and hair
      3. Puberty and sex differences a “long time coming”
    5. Evolving regional specializations
      1. Hair, nails and glands
      2. Sensory receptors, end organs and dermatomes
      3. Ectodysplasin signaling
    6. Evolutionary changes in development
      1. The skin genes we share with animals
      2. Common evolutionary signaling mechanisms
      3. The evolution of the mammary gland
  3. The evolved function of skin colour
    1. Geographic and seasonal gradations of ultraviolet (UV) exposure
    2. Protecting the exposed skin from UV damage
    3. Tanning response to exposure
    4. Melanocytes evolved as both our friend and enemy
  4. Evolved functions of the skin in Vitamin D production
    1. Vitamin D normal functions
    2. Vitamin D deficiency, an evolutionary selection agent?
  5. Hairlessness in humans
    1. The different types of hair
    2. The hair follicle phases (anagen, catagen and telogen)
  6. The evolving diseases of the skin
    1. The cancers basal cell carcinoma, squamous cell carcinoma, and malignant melanoma and breast cancer
    2. The now common infections of the skin
    3. Mosquitoes and malaria, “once bitten, twice shy”
    4. Modern disease HIV/Aids and the skin
      1. Viruses herpes and Kaposi sarcoma, Molluscum contagiosum
      2. Fungi candida fungus (thrush) infections
      3. Photodermatitis and Prurigo nodularis
    5. The changing environment and skin infections
      1. The evolving antibiotic and fungicide resistance
      2. The effects of global warming changes
  7. The evolving future of skin
    1. Stem cells of the skin
    2. Evolution of the ageing skin

Predicting the future of skin in the 22nd century

Defining the cellular lineage hierarchy in the interfollicular epidermis of adult skin

Nat Cell Biol. 2016 Jun;18(6):619-31. doi: 10.1038/ncb3359. Epub 2016 May 16.

Sada A1, Jacob F1, Leung E1, Wang S1, White BS2,3, Shalloway D1, Tumbar T1.


The interfollicular epidermis regenerates from heterogeneous basal skin cell populations that divide at different rates. It has previously been presumed that infrequently dividing basal cells known as label-retaining cells (LRCs) are stem cells, whereas non-LRCs are short-lived progenitors. Here we employ the H2B-GFP pulse-chase system in adult mouse skin and find that epidermal LRCs and non-LRCs are molecularly distinct and can be differentiated by Dlx1(CreER) and Slc1a3(CreER) genetic marking, respectively. Long-term lineage tracing and mathematical modelling of H2B-GFP dilution data show that LRCs and non-LRCs constitute two distinct stem cell populations with different patterns of proliferation, differentiation and upward cellular transport. During homeostasis, these populations are enriched in spatially distinct skin territories and can preferentially produce unique differentiated lineages. On wounding or selective killing, they can temporarily replenish each other's territory. These two discrete interfollicular stem cell populations are functionally interchangeable and intrinsically well adapted to thrive in distinct skin environments.

PMID 27183471


Transcription factor p63 bookmarks and regulates dynamic enhancers during epidermal differentiation

EMBO Rep. 2015 Jun 1. pii: e201439941. [Epub ahead of print]

Kouwenhoven EN1, Oti M2, Niehues H3, van Heeringen SJ2, Schalkwijk J3, Stunnenberg HG4, van Bokhoven H5, Zhou H6.


The transcription factor p63 plays a pivotal role in keratinocyte proliferation and differentiation in the epidermis. However, how p63 regulates epidermal genes during differentiation is not yet clear. Using epigenome profiling of differentiating human primary epidermal keratinocytes, we characterized a catalog of dynamically regulated genes and p63-bound regulatory elements that are relevant for epithelial development and related diseases. p63-bound regulatory elements occur as single or clustered enhancers, and remarkably, only a subset is active as defined by the co-presence of the active enhancer mark histone modification H3K27ac in epidermal keratinocytes. We show that the dynamics of gene expression correlates with the activity of p63-bound enhancers rather than with p63 binding itself. The activity of p63-bound enhancers is likely determined by other transcription factors that cooperate with p63. Our data show that inactive p63-bound enhancers in epidermal keratinocytes may be active during the development of other epithelial-related structures such as limbs and suggest that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates genes through temporal- and spatial-specific active enhancers. © 2015 The Authors. Published under the terms of the CC BY NC ND 4.0 license. KEYWORDS: epidermal differentiation; epigenomics; gene regulation; p63

PMID 26034101


Wnt11 is required for oriented migration of dermogenic progenitor cells from the dorsomedial lip of the avian dermomyotome

PLoS One. 2014 Mar 26;9(3):e92679. doi: 10.1371/journal.pone.0092679. eCollection 2014.

Morosan-Puopolo G1, Balakrishnan-Renuka A1, Yusuf F2, Chen J2, Dai F3, Zoidl G2, Lüdtke TH4, Kispert A4, Theiss C2, Abdelsabour-Khalaf M5, Brand-Saberi B6. Author information

Abstract The embryonic origin of the dermis in vertebrates can be traced back to the dermomyotome of the somites, the lateral plate mesoderm and the neural crest. The dermal precursors directly overlying the neural tube display a unique dense arrangement and are the first to induce skin appendage formation in vertebrate embryos. These dermal precursor cells have been shown to derive from the dorsomedial lip of the dermomyotome (DML). Based on its expression pattern in the DML, Wnt11 is a candidate regulator of dorsal dermis formation. Using EGFP-based cell labelling and time-lapse imaging, we show that the Wnt11 expressing DML is the source of the dense dorsal dermis. Loss-of-function studies in chicken embryos show that Wnt11 is indeed essential for the formation of dense dermis competent to support cutaneous appendage formation. Our findings show that dermogenic progenitors cannot leave the DML to form dense dorsal dermis following Wnt11 silencing. No alterations were noticeable in the patterning or in the epithelial state of the dermomyotome including the DML. Furthermore, we show that Wnt11 expression is regulated in a manner similar to the previously described early dermal marker cDermo-1. The analysis of Wnt11 mutant mice exhibits an underdeveloped dorsal dermis and strongly supports our gene silencing data in chicken embryos. We conclude that Wnt11 is required for dense dermis and subsequent cutaneous appendage formation, by influencing the cell fate decision of the cells in the DML.

PMID 24671096


Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development

Arch Dermatol Res. 2013 Jul;305(5):379-87. doi: 10.1007/s00403-013-1319-8. Epub 2013 Feb 3.

Gkegkes ID1, Aroni K, Agrogiannis G, Patsouris ES, Konstantinidou AE.


Caspase-14 is a seemingly non-apoptotic caspase involved in keratinocyte differentiation and cornification of the skin. Keratin-19 is an epithelial marker and a potential marker of epidermal stem cells that is expressed during human fetal skin development. We examined the immunohistochemical expression of caspase-14 in relation to CK-19 in the human fetal skin during development and perinatally, to assess their role in human skin maturation. Skin samples were received at autopsy. In the fetal epidermis, caspase-14 was predominantly expressed in the more differentiated layers, gradually disappearing from the basal layer toward term. By contrast, keratin-19 expression gradually decreased with epidermal maturation through gestation (rho = -0.949; p = 0.0001) and was a marker of the germinative layers. Keratin-19 was preserved in scarce basal cell nests at term and postnatally. Caspase-14 and keratin-19 were inversely expressed in the differentiating epidermal layers through gestation (p < 0.0001). Concerning the appendages, in hair follicles and sebaceous glands, caspase-14 located preferentially in the more differentiated layers of the inner root sheath, whereas keratin-19 was expressed in the outer sheath. Eccrine sweat glands showed a variable pattern of caspase-14 and keratin-19 expression. In conclusion, caspase-14 emerged as a marker of human skin differentiation during development, while keratin-19 marked the germinative epithelial layers in the fetal epidermis and appendages and possibly the nests of epidermal stem cells.

PMID: 23377137 DOI: 10.1007/s00403-013-1319-8


In vitro dedifferentiation of melanocytes from adult epidermis

PLoS One. 2011 Feb 23;6(2):e17197. doi: 10.1371/journal.pone.0017197.

Kormos B1, Belso N, Bebes A, Szabad G, Bacsa S, Széll M, Kemény L, Bata-Csörgo Z.


In previous work we described a novel culture technique using a cholera toxin and PMA-free medium (Mel-mix) for obtaining pure melanocyte cultures from human adult epidermis. In Mel-mix medium the cultured melanocytes are bipolar, unpigmented and highly proliferative. Further characterization of the cultured melanocytes revealed the disappearance of c-Kit and TRP-1 and induction of nestin expression, indicating that melanocytes dedifferentiated in this in vitro culture. Cholera toxin and PMA were able to induce c-Kit and TRP-1 protein expressions in the cells, reversing dedifferentiation. TRP-1 mRNA expression was induced in dedifferentiated melanocytes by UV-B irradiated keratinocyte supernatants, however direct UV-B irradiation of the cells resulted in further decrease of TRP-1 mRNA expression. These dedifferentiated, easily accessible cultured melanocytes provide a good model for studying melanocyte differentiation and possibly transdifferentiation. Because melanocytes in Mel-mix medium can be cultured with human serum as the only supplement, this culture system is also suitable for autologous cell transplantation. PMID: 21383848 PMCID: PMC3044174 DOI: 10.1371/journal.pone.0017197 [Indexed for MEDLINE] Free PMC Article

Neonatal skin maturation--vernix caseosa and free amino acids

Pediatr Dermatol. 2011 Mar-Apr;28(2):122-32. doi: 10.1111/j.1525-1470.2011.01309.x.

Visscher MO, Utturkar R, Pickens WL, LaRuffa AA, Robinson M, Wickett RR, Narendran V, Hoath SB. Source The Skin Sciences Institute, Division of Neonatology and Pulmonary Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.


Neonatal skin hydration decreases rapidly postnatally and then increases, indicating adaptive changes in stratum corneum water handling properties. Transition from high to low humidity at birth may initiate filaggrin proteolysis to free amino acids. Neonatal skin with vernix caseosa retained is more hydrated than skin with vernix removed. This study examines the potential roles of free amino acids and vernix in postnatal adaptation of infant stratum corneum in vivo. Specifically, the ontogeny of free amino acid generation in neonatal stratum corneum and the role of vernix caseosa in postnatal adaptation were examined using high performance liquid chromatography. Free amino acids were quantified for infant skin samples collected at (i) birth and 1 month and (ii) birth and 24 hours after vernix caseosa retention or removal and compared to neonatal foreskin, vernix caseosa, and adult stratum corneum using t-tests, analysis of variance, or univariate procedures. Free amino acids were extremely low at birth, significantly higher 1 month later but lower than in adults. Vernix caseosa retention led to significantly higher free amino acids 24 hours after birth compared to infants with vernix caseosa removed, and it paralleled the higher stratum corneum hydration of vernix caseosa-retained skin. Vernix caseosa contained free amino acids, with glutamic acid and histidine levels higher than in infants. Free amino acids in vernix caseosa-retained skin appear to originate from vernix caseosa. Free amino acids were lower in neonatal foreskin than adult forearm stratum corneum. Arginine was higher than citrulline at birth, but levels were comparable in older infants. The free amino acid increase at 1 month may be initiated by the humidity transition at birth and supports results in animals. The findings have implications for infant skin care practices.

© 2011 Wiley Periodicals, Inc.

PMID 21504444


Role of canonical Wnt signaling/ß-catenin via Dermo1 in cranial dermal cell development

Development. 2010 Dec;137(23):3973-84. Epub 2010 Oct 27.

Tran TH, Jarrell A, Zentner GE, Welsh A, Brownell I, Scacheri PC, Atit R.

Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA. Abstract Cranial dermis develops from cephalic mesoderm and neural crest cells, but what signal(s) specifies the dermal lineage is unclear. Using genetic tools to fate map and manipulate a cranial mesenchymal progenitor population in the supraorbital region, we show that the dermal progenitor cells beneath the surface ectoderm process canonical Wnt signaling at the time of specification. We show that Wnt signaling/β-catenin is absolutely required and sufficient for Dermo1 expression and dermal cell identity in the cranium. The absence of the Wnt signaling cue leads to formation of cartilage in craniofacial and ventral trunk regions at the expense of dermal and bone lineages. Dermo1 can be a direct transcription target and may mediate the functional role of Wnt signaling in dermal precursors. This study reveals a lineage-specific role of canonical Wnt signaling/β-catenin in promoting dermal cell fate in distinct precursor populations.

PMID: 20980404

Comparison between human fetal and adult skin

Coolen NA, Schouten KC, Middelkoop E, Ulrich MM. Arch Dermatol Res. 2010 Jan;302(1):47-55. Epub 2009 Aug 23. PMID: 19701759

Healing of early-gestation fetal wounds results in scarless healing. Since the capacity for regeneration is probably inherent to the fetal skin itself, knowledge of the fetal skin composition may contribute to the understanding of fetal wound healing. The aim of this study was to analyze the expression profiles of different epidermal and dermal components in the human fetal and adult skin. In the human fetal skin (ranging from 13 to 22 weeks’ gestation) and adult skin biopsies, the expression patterns of several epidermal proteins (K10, K14, K16, K17, SKALP, involucrin), basement membrane proteins, Ki-67, blood vessels and extracellular matrix proteins (fibronectin, chondroitin sulfate, elastin) were determined using immunohistochemistry. The expression profiles of K17, involucrin, dermal Ki-67, fibronectin and chondroitin sulfate were higher in the fetal skin than in adult skin. In the fetal skin, elastin was not present in the dermis, but it was found in the adult skin. The expression patterns of basement membrane proteins, blood vessels, K10, K14, K16 and epidermal Ki-67 were similar in human fetal skin and adult skin. In this systematic overview, most of the differences between fetal and adult skin were found at the level of dermal extracellular matrix molecules expression. This study suggests that, especially, dermal components are important in fetal scarless healing.

Development of a three dimensional multiscale computational model of the human epidermis

Adra S, Sun T, MacNeil S, Holcombe M, Smallwood R. PLoS One. 2010 Jan 14;5(1):e8511. PMID: 20076760

Transforming Growth Factor (TGF-beta1) is a member of the TGF-beta superfamily ligand-receptor network. and plays a crucial role in tissue regeneration. The extensive in vitro and in vivo experimental literature describing its actions nevertheless describe an apparent paradox in that during re-epithelialisation it acts as proliferation inhibitor for keratinocytes. The majority of biological models focus on certain aspects of TGF-beta1 behaviour and no one model provides a comprehensive story of this regulatory factor's action. Accordingly our aim was to develop a computational model to act as a complementary approach to improve our understanding of TGF-beta1. In our previous study, an agent-based model of keratinocyte colony formation in 2D culture was developed. In this study this model was extensively developed into a three dimensional multiscale model of the human epidermis which is comprised of three interacting and integrated layers: (1) an agent-based model which captures the biological rules governing the cells in the human epidermis at the cellular level and includes the rules for injury induced emergent behaviours, (2) a COmplex PAthway SImulator (COPASI) model which simulates the expression and signalling of TGF-beta1 at the sub-cellular level and (3) a mechanical layer embodied by a numerical physical solver responsible for resolving the forces exerted between cells at the multi-cellular level. The integrated model was initially validated by using it to grow a piece of virtual epidermis in 3D and comparing the in virtuo simulations of keratinocyte behaviour and of TGF-beta1 signalling with the extensive research literature describing this key regulatory protein. This research reinforces the idea that computational modelling can be an effective additional tool to aid our understanding of complex systems. In the accompanying paper the model is used to explore hypotheses of the functions of TGF-beta1 at the cellular and subcellular level on different keratinocyte populations during epidermal wound healing.

PMID: 20076760


Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network

Chorro L, Sarde A, Li M, Woollard KJ, Chambon P, Malissen B, Kissenpfennig A, Barbaroux JB, Groves R, Geissmann F. J Exp Med. 2009 Dec 21;206(13):3089-100. Epub 2009 Dec 7. PMID: 19995948

Most tissues develop from stem cells and precursors that undergo differentiation as their proliferative potential decreases. Mature differentiated cells rarely proliferate and are replaced at the end of their life by new cells derived from precursors. Langerhans cells (LCs) of the epidermis, although of myeloid origin, were shown to renew in tissues independently from the bone marrow, suggesting the existence of a dermal or epidermal progenitor. We investigated the mechanisms involved in LC development and homeostasis. We observed that a single wave of LC precursors was recruited in the epidermis of mice around embryonic day 18 and acquired a dendritic morphology, major histocompatibility complex II, CD11c, and langerin expression immediately after birth. Langerin(+) cells then undergo a massive burst of proliferation between postnatal day 2 (P2) and P7, expanding their numbers by 10-20-fold. After the first week of life, we observed low-level proliferation of langerin(+) cells within the epidermis. However, in a mouse model of atopic dermatitis (AD), a keratinocyte signal triggered increased epidermal LC proliferation. Similar findings were observed in epidermis from human patients with AD. Therefore, proliferation of differentiated resident cells represents an alternative pathway for development in the newborn, homeostasis, and expansion in adults of selected myeloid cell populations such as LCs. This mechanism may be relevant in locations where leukocyte trafficking is limited.

PMID: 19995948

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at

Elaine Fuchs: A love for science that's more than skin deep. Interviewed by Ben Short

Fuchs E. J Cell Biol. 2009 Dec 28;187(7):938-9. No abstract available. PMID: 20038675

FGF-regulated BMP signaling is required for eyelid closure and to specify conjunctival epithelial cell fate

Development. 2009 May;136(10):1741-50. Epub 2009 Apr 15.

Huang J, Dattilo LK, Rajagopal R, Liu Y, Kaartinen V, Mishina Y, Deng CX, Umans L, Zwijsen A, Roberts AB, Beebe DC.

Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO 63130, USA. Abstract There are conflicting reports about whether BMP signaling is required for eyelid closure during fetal development. This question was addressed using mice deficient in BMP or TGFbeta signaling in prospective eyelid and conjunctival epithelial cells. Genes encoding two type I BMP receptors, the type II TGFbeta receptor, two BMP- or two TGFbeta-activated R-Smads or the co-Smad Smad4 were deleted from the ocular surface ectoderm using Cre recombinase. Only mice with deletion of components of the BMP pathway had an 'eyelid open at birth' phenotype. Mice lacking Fgf10 or Fgfr2 also have open eyelids at birth. To better understand the pathways that regulate BMP expression and function during eyelid development, we localized BMPs and BMP signaling intermediates in Fgfr2 and Smad4 conditional knockout (CKO) mice. We found that Fgfr2 was required for the expression of Bmp4, the normal distribution of Shh signaling and for preserving the differentiation of the conjunctival epithelium. FGF signaling also promoted the expression of the Wnt antagonist Sfrp1 and suppressed Wnt signaling in the prospective eyelid epithelial cells, independently of BMP function. Transcripts encoding Foxc1 and Foxc2, which were previously shown to be necessary for eyelid closure, were not detectable in Smad4(CKO) animals. c-Jun, another key regulator of eyelid closure, was present and phosphorylated in eyelid periderm cells at the time of fusion, but failed to translocate to the nucleus in the absence of BMP function. Smad4(CKO) mice also showed premature differentiation of the conjunctival epithelium, conjunctival hyperplasia and the acquisition of epidermal characteristics, including formation of an ectopic row of hair follicles in place of the Meibomian glands. A second row of eyelashes is a feature of human lymphedema-distichiasis syndrome, which is associated with mutations in FOXC2.

PMID 19369394


Unraveling the mystery of vernix caseosa

Indian J Dermatol. 2008;53(2):54-60.

Singh G, Archana G. Source Department of Dermatology and STD, Sri Devaraj Urs Medical College, Tamaka, Kolar - 563 101, India.


Vernix caseosa is a white, creamy, naturally occurring biofilm covering the skin of the fetus during the last trimester of pregnancy. Vernix coating on the neonatal skin protects the newborn skin and facilitates extra-uterine adaptation of skin in the first postnatal week if not washed away after birth. It consists of water-containing corneocytes embedded in a lipid matrix. The strategic location of the vernix on the fetal skin surface suggests participation in multiple overlapping functions required at birth, such as barrier to water loss, temperature regulation, and innate immunity. Vernix seems to perform various integral roles during transition of the fetus from intra-uterine to extra-uterine life. It has also found various interesting diagnostic and prognostic implications in this arena. Thus, it continues to be an intriguing topic of interest among the medical fraternity to understand its detailed biology and function in the fetus and also to put its naturally endowed characteristics to use in the adult population.

PMID 19881987


Integrin expression during human epidermal development in vivo and in vitro

Development. 1991 May;112(1):193-206.

Hertle MD, Adams JC, Watt FM. Source Keratinocyte Laboratory, Imperial Cancer Research Fund, London, UK. Abstract In order to investigate the role of extracellular matrix receptors of the integrin family in establishing the spatial organization of epidermal kerotinocytes, we used immunofluorescence microscopy to examine the expression of a range of integrin subunits during development of human palm and sole skin. All of the integrins expressed during development were also present in mature epidermis and were largely confined to the basal layer of keratinocytes in a pericellular distribution. The alpha 3 and beta 1 subunits were expressed prior to the initiation of stratification and did not change in abundance or distribution during subsequent development. alpha 4 and beta 3 were not detected at any time in the epidermis. Every other subunit examined showed spatial or temporal changes in expression. Staining for alpha 1 was strong before stratification and until mid-development, but was greatly decreased in neonatal epidermis. alpha 2 was first detected in small patches of basal cells prior to stratification, and thereafter was found in the entire basal layer, with greater staining in developing sweat glands. alpha 5 was not expressed until mid-development, and then primarily in developing sweat glands, with faint expression in neonatal epidermis. alpha v was detected following stratification, in developing sweat glands, and occasionally in neonatal epidermis. alpha 6 and beta 4 were peribasally expressed before stratification, but thereafter became concentrated at the basal cell surface in contact with the basement membrane, co-localizing with hemidesmosomes as determined by staining with bullous pemphigoid antiserum. We also examined the distribution of three known ligands for keratinocyte integrins: laminin and collagen type IV were present in the basement membrane zone at all stages of development, whereas fibronectin was only evident there until about 13 weeks estimated gestational age. Finally, we found that the changes in integrin expression that occur on initiation of stratification in vivo could be reproduced in organ cultures of developing skin; such cultures therefore provided a useful experimental model for further studies of the role of integrins in epidermal stratification.

PMID 1769328

Biology and Genetics of Hair.


Transient receptor potential channel - (TRP) a transmembrane protein acting as a thermo-sensitive channel that is expressed on sensory neurons and skin epithelial cells in vertebrate and non-vertebrate animals.


Ex vivo live imaging of melanoblast migration in embryonic mouse skin.

Pigment Cell Melanoma Res. 2010 Apr;23(2):299-301. Epub 2010 Jan 7.

Mort RL, Hay L, Jackson IJ.

PMID: 20067551

Melanoblasts are the embryonic precursors of melanocytes. They are derived from the neural crest at around embryonic day 9.5 (E9.5) and upregulate early melanoblast specific markers (Mitf, Tyrosinase, Dct, Kit) around E10.5.

Includes videos of melanoblast migration in model mouse skin system.

The making of a melanocyte: the specification of melanoblasts from the neural crest.

Thomas AJ, Erickson CA. Pigment Cell Melanoma Res. 2008 Dec;21(6):598-610. Review. PMID: 19067969

Two distinct types of mouse melanocyte: differential signaling requirement for the maintenance of non-cutaneous and dermal versus epidermal melanocytes

Development. 2009 Aug;136(15):2511-21. Epub 2009 Jun 24.

Aoki H, Yamada Y, Hara A, Kunisada T.

Department of Tissue and Organ Development, Regeneration, and Advanced Medical Science, Gifu University Graduate School of Medicine, Yanagido, Gifu, Japan. Abstract Unlike the thoroughly investigated melanocyte population in the hair follicle of the epidermis, the growth and differentiation requirements of the melanocytes in the eye, harderian gland and inner ear - the so-called non-cutaneous melanocytes - remain unclear. In this study, we investigated the in vitro and in vivo effects of the factors that regulate melanocyte development on the stem cells or the precursors of these non-cutaneous melanocytes. In general, a reduction in KIT receptor tyrosine kinase signaling leads to disordered melanocyte development. However, melanocytes in the eye, ear and harderian gland were revealed to be less sensitive to KIT signaling than cutaneous melanocytes. Instead, melanocytes in the eye and harderian gland were stimulated more effectively by endothelin 3 (ET3) or hepatocyte growth factor (HGF) signals than by KIT signaling, and the precursors of these melanocytes expressed the lowest amount of KIT. The growth and differentiation of these non-cutaneous melanocytes were specifically inhibited by antagonists for ET3 and HGF. In transgenic mice induced to express ET3 or HGF in their skin and epithelial tissues from human cytokeratin 14 promoters, the survival and differentiation of non-cutaneous and dermal melanocytes, but not epidermal melanocytes, were enhanced, apparently irrespective of KIT signaling. These results provide a molecular basis for the clear discrimination between non-cutaneous or dermal melanocytes and epidermal melanocytes, a difference that might be important in the pathogenesis of melanocyte-related diseases and melanomas.

PMID: 19553284

AP-2 factors act in concert with Notch to orchestrate terminal differentiation in skin epidermis

J Cell Biol. 2008 Oct 6;183(1):37-48. Epub 2008 Sep 29.

Wang X, Pasolli HA, Williams T, Fuchs E.

The Howard Hughes Medical Institute and Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065, USA. Abstract The mechanisms by which mammalian epidermal stem cells cease to proliferate and embark upon terminal differentiation are still poorly understood. By conditionally ablating two highly expressed transcription factors, AP-2alpha and AP-2gamma, we unmasked functional redundancies and discovered an essential role for AP-2s in the process. In vivo and in vitro, AP-2 deficiency is accompanied by surprisingly minimal changes in basal gene expression but severely perturbed terminal differentiation and suppression of additional transcription factors and structural genes involved. In dissecting the underlying molecular pathways, we uncover parallel pathways involving AP-2 and Notch signaling, which converge to govern CCAAT/enhancer binding protein genes and orchestrate the transition from basal proliferation to suprabasal differentiation. Finally, we extend the striking similarities in compromising either Notch signaling or AP-2alpha/AP-2gamma in developing skin to that in postnatal skin, where all hair follicles and sebaceous gland differentiation are also repressed and overt signs of premalignant conversion emerge.

PMID: 18824566


Cell Death Differ. 1998 Oct;5(10):838-46. Identification of a new caspase homologue: caspase-14.

Van de Craen M1, Van Loo G, Pype S, Van Criekinge W, Van den brande I, Molemans F, Fiers W, Declercq W, Vandenabeele P. Author information Abstract Caspases are cysteinyl aspartate-specific proteinases, many of which play a central role in apoptosis. Here, we report the identification of a new murine caspase homologue, viz. caspase-14. It is most related to human/murine caspase-2 and human caspase-9, possesses all the typical amino acid residues of the caspases involved in catalysis, including the QACRG box, and contains no or only a very short prodomain. Murine caspase-14 shows 83% similarity to human caspase-14. Human caspase-14 is assigned to chromosome 19p13.1. Northern blot analysis revealed that mRNA expression of caspase-14 is undetectable in all mouse adult tissues examined except for skin, while it is abundantly expressed in mouse embryos. In contrast to many other caspase family members, murine caspase-14 is not cleaved by granzyme B, caspase-1, caspase-2, caspase-3, caspase-6, caspase-7 or caspase-11, but is weakly processed into p18 and p11 subunits by murine caspase-8. No aspartase activity of murine caspase-14 could be generated by bacterial or yeast expression. Transient overexpression of murine caspase-14 in mammalian cells did not elicit cell death and did not interfere with caspase-8-induced apoptosis. In conclusion, caspase-14 is a member of the caspase family but no proteolytic or biological activities have been identified so far. The high constitutive expression levels in embryos and specific expression in adult skin suggest a role in ontogenesis and skin physiology.

PMID: 10203698 DOI: 10.1038/sj.cdd.4400444


Patterns of type VI collagen compared to types I, III and V collagen in human embryonic and fetal skin and in fetal skin-derived cell cultures

Matrix Biol. 1994 Mar;14(2):159-70.

Smith LT.


The distribution of type VI collagen was examined in human embryonic and fetal skin and in cultured cells and matrix from this tissue. Frozen sections were immunolabeled with primary antibodies against type VI collagen and types I, III or V collagen, and processed further for fluorescence microscopy and immunoelectron microscopy. At 6 weeks estimated gestational age (EGA), type VI collagen was identified by positive fluorescence and by immunogold staining of filaments and fibers beneath the dermal-epidermal junction (DEJ), weaker fluorescence in the fine matrix of the dermis, and stronger fluorescence in the subcutis. At progressive stages of gestation, immunolabeling for type VI collagen increased in the dermis in parallel with increased deposition of types I and III collagen. By 15 weeks EGA, type VI collagen stained intensely throughout the dermis. At 13 weeks EGA, type VI collagen appeared diminished from the growing tips of invaginating hair buds, but as the hair peg developed, type VI collagen accumulated in adnexal sheaths. Cell cultures were derived from fetal skin at 7.5 to 12 weeks EGA. In primary explant cultures containing both keratinocytes and fibroblasts, mats of type V collagen were present beneath keratinocytes and associated with dense spots that co-labeled for both type VI and type V collagen. In passaged cultures of fibroblasts, individual cells with or without pretreatment with monensin were positive for type VI and/or types I, III or V collagen. Fibrous matrix that was labeled for type VI collagen was also immunopositive for type I or III collagen, while filamentous matrix that was type VI collagen positive tended to exclude types I and III collagen but in some areas to overlap with type V collagen. These findings support the hypothesis that type VI collagen present in both filamentous and fibrous matrix and networks of type VI collagen may serve as a fine scaffolding that facilitates the integration of types I and III collagen into developing fibrous matrix.

PMID: 8061928


Fibrous matrix that was labeled for type VI collagen was also immunopositive for type I or III collagen, while filamentous matrix that was type VI collagen positive tended to exclude types I and III collagen but in some areas to overlap with type V collagen. These findings support the hypothesis that type VI collagen present in both filamentous and fibrous matrix and networks of type VI collagen may serve as a fine scaffolding that facilitates the integration of types I and III collagen into developing fibrous matrix.

The dermis is located beneath the epidermis and is the thickest of the three layers of the skin (1.5 to 4 mm thick), making up approximately 90 percent of the thickness of the skin. The main functions of the dermis are to regulate temperature and to supply the epidermis with nutrient-saturated blood. Much of the body's water supply is stored within the dermis. This layer contains most of the skins' specialized cells and structures, including:

The Dermis

The dermis is located beneath the epidermis and is the thickest of the three layers of the skin (1.5 to 4 mm thick), making up approximately 90 percent of the thickness of the skin. The main functions of the dermis are to regulate temperature and to supply the epidermis with nutrient-saturated blood. Much of the body's water supply is stored within the dermis. This layer contains most of the skins' specialized cells and structures, including:

Blood Vessels The blood vessels supply nutrients and oxygen to the skin and take away cell waste and cell products. The blood vessels also transport the vitamin D produced in the skin back to the rest of the body.

Lymph Vessels The lymph vessels bathe the tissues of the skin with lymph, a milky substance that contains the infection-fighting cells of the immune system. These cells work to destroy any infection or invading organisms as the lymph circulates to the lymph nodes.

Hair Follicles The hair follicle is a tube-shaped sheath that surrounds the part of the hair that is under the skin and nourishes the hair.

Sweat Glands The average person has about 3 million sweat glands. Sweat glands are classified according to two types: Apocrine glands are specialized sweat glands that can be found only in the armpits and pubic region. These glands secrete a milky sweat that encourages the growth of the bacteria responsible for body odor. Eccrine glands are the true sweat glands. Found over the entire body, these glands regulate body temperature by bringing water via the pores to the surface of the skin, where it evaporates and reduces skin temperature. These glands can produce up to two liters of sweat an hour, however, they secrete mostly water, which doesn't encourage the growth of odor-producing bacteria.

Sebaceous glands Sebaceous, or oil, glands, are attached to hair follicles and can be found everywhere on the body except for the palms of the hands and the soles of the feet. These glands secrete oil that helps keep the skin smooth and supple. The oil also helps keep skin waterproof and protects against an overgrowth of bacteria and fungi on the skin.

Nerve Endings The dermis layer also contains pain and touch receptors that transmit sensations of pain, itch, pressure and information regarding temperature to the brain for interpretation. If necessary, shivering (involuntary contraction and relaxation of muscles) is triggered, generating body heat.

Collagen and Elastin The dermis is held together by a protein called collagen, made by fibroblasts. Fibroblasts are skin cells that give the skin its strength and resilience. Collagen is a tough, insoluble protein found throughout the body in the connective tissues that hold muscles and organs in place. In the skin, collagen supports the epidermis, lending it its durability. Elastin, a similar protein, is the substance that allows the skin to spring back into place when stretched and keeps the skin flexible.

The dermis layer is made up of two sublayers:

The Papillary Layer

The upper, papillary layer, contains a thin arrangement of collagen fibers. The papillary layer supplies nutrients to select layers of the epidermis and regulates temperature. Both of these functions are accomplished with a thin, extensive vascular system that operates similarly to other vascular systems in the body. Constriction and expansion control the amount of blood that flows through the skin and dictate whether body heat is dispelled when the skin is hot or conserved when it is cold.

The Reticular Layer

The lower, reticular layer, is thicker and made of thick collagen fibers that are arranged in parallel to the surface of the skin. The reticular layer is denser than the papillary dermis, and it strengthens the skin, providing structure and elasticity. It also supports other components of the skin, such as hair follicles, sweat glands, and sebaceous glands.

The Subcutis

The subcutis is the innermost layer of the skin, and consists of a network of fat and collagen cells. The subcutis is also known as the hypodermis or subcutaneous layer, and functions as both an insulator, conserving the body's heat, and as a shock-absorber, protecting the inner organs. It also stores fat as an energy reserve for the body. The blood vessels, nerves, lymph vessels, and hair follicles also cross through this layer. The thickness of the subcutis layer varies throughout the body and from person to person.