a primary reason for this perspective is to highlight the utility of in vivo model systems , and specifically the skin , in studies of basic cell biological regulators . for basic cell biologists looking for in vivo systems to expand into , the skin offers a combination of advantages that other tissues do not possess . we discuss these , along with examples of success stories in which research in skin has uncovered mechanisms of basic cell biology , most prominently in the understanding of the cell adhesion / intermediate filament systems . in addition , we discuss how genetic studies often reveal unexpected phenotypes and roles for cell biological regulators . these are especially enlightening and often yield insights into novel functions for core machinery and additional levels of regulation . although we focus on the skin as a useful model , it is important to emphasize that cell biological machinery is adapted for diverse functions in different tissues . therefore lessons learned in cultured cells and in studies of the skin may not necessarily explain the complexity of how these proteins function and interact within a different tissue context . in addition , this is clearly a two - way street , as more cell biological studies on the skin will increase our understanding of the physiology and pathology of this essential organ . advantages of using of the skin as a model system include the following : 
 accessibility for microscopy . the medical study of the skin and its diseases has a long history because the skin , being on the body surface , could be described and catalogued before present imaging technologies and surgical procedures were commonplace . this is also a boon to biologists , as it allows live microscopic analysis in living embryos or adults . imaging has allowed visualization of diverse phenomena , including immune cell recruitment to invading pathogens , stages of hair follicle morphogenesis , migration of melanoblasts , and the dynamics of cell adhesion turnover , to name just a few ( peters et  al . , 2008 ; mort et  al . , 2010 ; rompolas et  al . , 2012 ; foote et  al . , techniques such as spinning disk microscopy are sufficient for some studies in the interfollicular epidermis , as the cells being imaged are very near the surface . in other cases , two - photon microscopy has been used to peer further into the skin . lightsheet microscopy promises to further propel these studies and our abilities to observe subcellular phenomena in tissues . this relies on the existence of transgenic mouse lines with fluorescent reporters  an emerging field in which the skin is well positioned to play a vital role.genetic tools and fluorescent transgenic lines . there are many genetic lines that allow the marking and lineage tracing of specific cell populations , as well as genetic fluorescent markers of signaling pathway activation . however , a toolkit of transgenic lines for the visualization of subcellular phenomena has also been gradually developing in the mouse ( table 1 ) . although we do not yet have the diversity of reporters found in flies and worms , the advent of genome editing technologies is expected to yield an ever - increasing set of reporters for the mouse . this is part of a larger collection of genetic tools made by researchers and global projects such as the knockout mouse project ( komp ) that allow the tissue and cell type  specific disruption or mis / overexpression of genes with existing alleles . in addition to these more traditional approaches , lentiviral infection of epidermal progenitors by in utero electroporation allows much more rapid analysis by both knockdown and misexpression analysis ( beronja et  al . first , there is an abundance of tissue when performing histological analyses , so there is more forgiveness for beginners ( no fine dissections and limitations of materials ) . of greater importance , the tissue abundance provides ample resources to facilitate biochemical studies . as an example , the initial identification of desmosomal cadherins was achieved through purification of desmosomes from a rich source : bovine muzzle epidermis ( drochmans et  al . . subsequent work would show that these are related to classical cadherins , that they form the adhesive core of desmosomes , and that some of them are targets for autoantibodies that disrupt desmosomes  a group of diseases known as pemphigus ( kottke et  al . in addition to traditional biochemical approaches , the skin is amenable to biochemical interaction screens and proteomic analysis , promising to further spur our understanding of cell biology.cell culture systems . the importance of the ability to culture and passage epidermal cells can not be overstated . through the pioneering work of howard green in the 1970s , we can isolate epidermal progenitors ( human and mouse ) , grow them for more detailed cell biological studies in vitro , and gain understanding of basic mechanisms . we can then take what we find back into the mouse to understand the physiology . although care must be taken in interpretation ( as cultured cells clearly exist in a very different environment from that in the tissue ) , such systems have proven to be invaluable tools in many studies . cultured cells can also be used to regrow stratified epidermis , a technique that can be used to generate a differentiated tissue from human cells as well as mouse cells . in addition , cultured cells can be engrafted back onto the mouse for analysis of genetically modified cells in a physiological environment.physiological readouts . , the different cell types require a multitude of fundamental biological processes to generate and maintain tissue function . in addition to readouts of tissue architecture , proliferation , and differentiation , we can also assess tissue function in a variety of ways , such as examination of the barrier activity of the epidermis . connecting basic cell biological regulators to tissue functions often provides surprises , as discussed later.clinical insights . in some cases , basic cell biology can be advanced by the existence of human mutations ( see examples in the next sections ) . the extensive descriptive work in dermatology , combined with new sequencing technologies , will allow the identification of genes and pathways that affect tissue architecture and function . the medical study of the skin and its diseases has a long history because the skin , being on the body surface , could be described and catalogued before present imaging technologies and surgical procedures were commonplace . this is also a boon to biologists , as it allows live microscopic analysis in living embryos or adults . imaging has allowed visualization of diverse phenomena , including immune cell recruitment to invading pathogens , stages of hair follicle morphogenesis , migration of melanoblasts , and the dynamics of cell adhesion turnover , to name just a few ( peters et  al . , 2008 ; mort et  al . , 2010 ; rompolas et  al . , 2012 ; foote et  al . , techniques such as spinning disk microscopy are sufficient for some studies in the interfollicular epidermis , as the cells being imaged are very near the surface . in other cases , two - photon microscopy has been used to peer further into the skin . lightsheet microscopy promises to further propel these studies and our abilities to observe subcellular phenomena in tissues . this relies on the existence of transgenic mouse lines with fluorescent reporters  an emerging field in which the skin is well positioned to play a vital role . there are many genetic lines that allow the marking and lineage tracing of specific cell populations , as well as genetic fluorescent markers of signaling pathway activation . however , a toolkit of transgenic lines for the visualization of subcellular phenomena has also been gradually developing in the mouse ( table 1 ) . although we do not yet have the diversity of reporters found in flies and worms , the advent of genome editing technologies is expected to yield an ever - increasing set of reporters for the mouse . this is part of a larger collection of genetic tools made by researchers and global projects such as the knockout mouse project ( komp ) that allow the tissue and cell type  specific disruption or mis / overexpression of genes with existing alleles . in addition to these more traditional approaches , lentiviral infection of epidermal progenitors by in utero electroporation allows much more rapid analysis by both knockdown and misexpression analysis ( beronja et  al . , 2010 ) . first , there is an abundance of tissue when performing histological analyses , so there is more forgiveness for beginners ( no fine dissections and limitations of materials ) . of greater importance , the tissue abundance provides ample resources to facilitate biochemical studies . as an example , the initial identification of desmosomal cadherins was achieved through purification of desmosomes from a rich source : bovine muzzle epidermis ( drochmans et  al . , 1978 ) . subsequent work would show that these are related to classical cadherins , that they form the adhesive core of desmosomes , and that some of them are targets for autoantibodies that disrupt desmosomes  a group of diseases known as pemphigus ( kottke et  al . in addition to traditional biochemical approaches , the skin is amenable to biochemical interaction screens and proteomic analysis , promising to further spur our understanding of cell biology . the importance of the ability to culture and passage epidermal cells can not be overstated . through the pioneering work of howard green in the 1970s , we can isolate epidermal progenitors ( human and mouse ) , grow them for more detailed cell biological studies in vitro , and gain understanding of basic mechanisms . we can then take what we find back into the mouse to understand the physiology . although care must be taken in interpretation ( as cultured cells clearly exist in a very different environment from that in the tissue ) , such systems have proven to be invaluable tools in many studies . cultured cells can also be used to regrow stratified epidermis , a technique that can be used to generate a differentiated tissue from human cells as well as mouse cells . in addition , cultured cells can be engrafted back onto the mouse for analysis of genetically modified cells in a physiological environment . physiological readouts . as such , the different cell types require a multitude of fundamental biological processes to generate and maintain tissue function . in addition to readouts of tissue architecture , proliferation , and differentiation , we can also assess tissue function in a variety of ways , such as examination of the barrier activity of the epidermis . connecting basic cell biological regulators to tissue functions often provides surprises , as discussed later . clinical insights . in some cases , basic cell biology can be advanced by the existence of human mutations ( see examples in the next sections ) . the extensive descriptive work in dermatology , combined with new sequencing technologies , will allow the identification of genes and pathways that affect tissue architecture and function . determination of the composition , functions , and pathologies associated with these cell adhesion systems are among the greatest successes of research in the skin . reverse genetic studies were the first to demonstrate a functional role for keratins in mechanical integrity of the skin ( vassar et  al . , 1991 ) , studies that were subsequently supported by analysis of human patients with mutations in keratins ( coulombe and lee , 2012 ) . continuing work has identified genetic lesions in many desmosomal proteins , hemidesmosomal proteins , and other keratins that lead to a spectrum of disorders not only in the skin , but also in the heart ( kottke et  al . , 2006 ) . in this case , the cell biology and the disease phenotypes have clear correlates  for example , the position of blistering ( between cells , within cells , or between cells and the basement membrane ) depends on where in this network the protein is localized and functioning . further studies on identification of components of the desmosomes , how they assemble , and how they connect to keratins have depended largely on experiments performed in cultured keratinocytes ( kowalczyk and green , 2013 ) . although there are many questions left to answer , the combination of tools and the clinical relevance of the findings will make the process particularly exciting . as an aside because this tissue experiences many physical insults , it is likely to continue to play an important role in understanding how cells / tissues sense and respond to force . k14 , keratin 14 promoter ; h2b , histone h2b ; gfp , green fluorescent protein ; emtb , ensconsin microtubule - binding domain ; nmiic , nonmuscle myosin iic ; zo-1 , zonula occludens 1 ; dpi , desmoplakin i ; numa , nuclear mitotic apparatus ; erk , extracellular signal regulated kinase ; fret , forster resonance energy transfer . one of the earliest examples of patient - directed research leading to deeper understanding of cell biological mechanisms is the study of xeroderma pigmentosum ( xp ) . the condition is a rare hereditary disease characterized by high sensitivity to ultraviolet ( uv ) radiation and increased susceptibility to cancers of the skin ( cleaver and bootsma , 1975 ) . cultured fibroblasts isolated from xp patients had impaired responses to the repair of double - stranded dna lesions after uv irradiation , a finding that was confirmed in vivo using tissue sections ( cleaver , 1968 ; epstein et  al . , 1970 ) . further studies revealed that these cells did not initiate the first step of nucleotide excision repair and that xp is caused by a failure to excise pyrimidine dimers after exposure of dna to uv ( setlow et  al . before these discoveries , the mechanisms that controlled dna repair had only been fully characterized in microorganisms ( cleaver , 1968 , 1978 ) . consequently , the examination of xp patient samples provided the first functional evidence for nucleotide excision repair in humans and on how defects in this process are associated with a clinical phenotype . mutations in other nucleotide excision repair genes lead to cockayne syndrome and trichothiodystrophy , disorders with both overlapping and distinct clinical features ( kraemer et  al . , 2007 ) . thus the genetics and cell biology continue to teach us about the roles of this pathway . determination of the composition , functions , and pathologies associated with these cell adhesion systems are among the greatest successes of research in the skin . reverse genetic studies were the first to demonstrate a functional role for keratins in mechanical integrity of the skin ( vassar et  al . , 1991 ) , studies that were subsequently supported by analysis of human patients with mutations in keratins ( coulombe and lee , 2012 ) . continuing work has identified genetic lesions in many desmosomal proteins , hemidesmosomal proteins , and other keratins that lead to a spectrum of disorders not only in the skin , but also in the heart ( kottke et  al . , 2006 ) . in this case , the cell biology and the disease phenotypes have clear correlates  for example , the position of blistering ( between cells , within cells , or between cells and the basement membrane ) depends on where in this network the protein is localized and functioning . further studies on identification of components of the desmosomes , how they assemble , and how they connect to keratins have depended largely on experiments performed in cultured keratinocytes ( kowalczyk and green , 2013 ) . although there are many questions left to answer , the combination of tools and the clinical relevance of the findings will make the process particularly exciting . as an aside because this tissue experiences many physical insults , it is likely to continue to play an important role in understanding how cells / tissues sense and respond to force . k14 , keratin 14 promoter ; h2b , histone h2b ; gfp , green fluorescent protein ; emtb , ensconsin microtubule - binding domain ; nmiic , nonmuscle myosin iic ; zo-1 , zonula occludens 1 ; dpi , desmoplakin i ; numa , nuclear mitotic apparatus ; erk , extracellular signal regulated kinase ; fret , forster resonance energy transfer . one of the earliest examples of patient - directed research leading to deeper understanding of cell biological mechanisms is the study of xeroderma pigmentosum ( xp ) . the condition is a rare hereditary disease characterized by high sensitivity to ultraviolet ( uv ) radiation and increased susceptibility to cancers of the skin ( cleaver and bootsma , 1975 ) . cultured fibroblasts isolated from xp patients had impaired responses to the repair of double - stranded dna lesions after uv irradiation , a finding that was confirmed in vivo using tissue sections ( cleaver , 1968 ; epstein et  al . , 1970 ) . further studies revealed that these cells did not initiate the first step of nucleotide excision repair and that xp is caused by a failure to excise pyrimidine dimers after exposure of dna to uv ( setlow et  al . the mechanisms that controlled dna repair had only been fully characterized in microorganisms ( cleaver , 1968 , 1978 ) . consequently , the examination of xp patient samples provided the first functional evidence for nucleotide excision repair in humans and on how defects in this process are associated with a clinical phenotype . mutations in other nucleotide excision repair genes lead to cockayne syndrome and trichothiodystrophy , disorders with both overlapping and distinct clinical features ( kraemer et  al . , 2007 ) . thus the genetics and cell biology continue to teach us about the roles of this pathway . the genetic analysis of core cell biological regulators often unveils unexpected or absent phenotypes . these studies can reveal unexpected additional functions for these proteins , uncover redundancy between different machineries , or expose additional levels of regulation that were previously unanticipated . p120-catenin is a well - studied adherens junction protein that functions to regulate cortical levels of e - cadherin ( davis et  al . , 2003 ; analysis of mutants lacking epidermal p120 , however , revealed phenotypes not associated with cell adhesion . instead , epidermal hyperplasia and chronic inflammation were induced by activation of the rho / nf-b axis ( perez - moreno et  al . , the arp2/3 complex generates branched actin networks that play diverse roles in cell migration , vesicle trafficking , and cell adhesion ( rotty et  al . , 2013 ) . surprisingly , loss of arp2/3 in the epidermis did not result in notable defects in cell architecture or adhesion . instead , arp2/3-complex mutant epidermis was hyperproliferative and showed defects in expression of both early and late differentiation genes . in addition , tight junction proteins showed decreased cortical organization in mutant tissue and did not generate robust resistance to ion flow in cell culture ( zhou et  al . , 2013 ) . for example , in intestinal epithelia , the arp2/3 complex regulates vesicle trafficking and the endolysosomal system ( zhou et  al . , 2015 ) . this highlights that different lessons will be learned by analysis of core cell biological regulators in diverse tissues . whereas par3 is believed to be a master regulator of epithelial polarity , the epidermis develops normally in its absence , highlighting our incomplete understanding of how polarity is generated in a mammalian tissue . loss of par3 , however , does have opposing effects on different tumor types , suppressing papillomas and promoting keratoacanthomas ( iden et  al . , 2012 ) . although the underlying mechanisms are not fully understood , this suggests that the epidermis will be useful for studying polarity signaling pathways and their role in both homeostasis and tumorigenesis . it also demonstrates that comparative studies of simple and stratified epithelia will identify conserved and divergent regulators of epithelial function . loss of reactive oxygen species through mutation of a transcription factor required for expression of electron transport chain components caused unexpected differentiation defects in the epidermis , presumably through defects in notch and wnt signaling , revealing additional roles for metabolic enzymes in tissue function ( hamanaka et  al . we have highlighted the utility of the skin as a model system , the different methodological approaches that can be used , and the types of information that can be gleaned from working with the skin . together these examples demonstrate that the skin is a powerful tool in which one can examine a wide array of cell biological phenomena . through continued collaborative efforts between cell biologists and skin biologists , we expect that additional fundamental insights into both basic cell biology and skin biology will continue to emerge .