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1.
Dev Cell ; 59(1): 20-32.e6, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38096824

RESUMO

Eccrine sweat glands are indispensable for human thermoregulation and, similar to other mammalian skin appendages, form from multipotent epidermal progenitors. Limited understanding of how epidermal progenitors specialize to form these vital organs has precluded therapeutic efforts toward their regeneration. Herein, we applied single-nucleus transcriptomics to compare the expression content of wild-type, eccrine-forming mouse skin to that of mice harboring a skin-specific disruption of Engrailed 1 (En1), a transcription factor that promotes eccrine gland formation in humans and mice. We identify two concurrent but disproportionate epidermal transcriptomes in the early eccrine anlagen: one that is shared with hair follicles and one that is En1 dependent and eccrine specific. We demonstrate that eccrine development requires the induction of a dermal niche proximal to each developing gland in humans and mice. Our study defines the signatures of eccrine identity and uncovers the eccrine dermal niche, setting the stage for targeted regeneration and comprehensive skin repair.


Assuntos
Glândulas Écrinas , Epiderme , Humanos , Camundongos , Animais , Epiderme/metabolismo , Glândulas Écrinas/metabolismo , Pele , Folículo Piloso/metabolismo , Regulação da Expressão Gênica , Mamíferos
2.
PLoS Genet ; 19(2): e1010614, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36745673

RESUMO

Enhancers are context-specific regulators of expression that drive biological complexity and variation through the redeployment of conserved genes. An example of this is the enhancer-mediated control of Engrailed 1 (EN1), a pleiotropic gene whose expression is required for the formation of mammalian eccrine sweat glands. We previously identified the En1 candidate enhancer (ECE) 18 cis-regulatory element that has been highly and repeatedly derived on the human lineage to potentiate ectodermal EN1 and induce our species' uniquely high eccrine gland density. Intriguingly, ECE18 quantitative activity is negligible outside of primates and ECE18 is not required for En1 regulation and eccrine gland formation in mice, raising the possibility that distinct enhancers have evolved to modulate the same trait. Here we report the identification of the ECE20 enhancer and show it has conserved functionality in mouse and human developing skin ectoderm. Unlike ECE18, knock-out of ECE20 in mice reduces ectodermal En1 and eccrine gland number. Notably, we find ECE20, but not ECE18, is also required for En1 expression in the embryonic mouse brain, demonstrating that ECE20 is a pleiotropic En1 enhancer. Finally, that ECE18 deletion does not potentiate the eccrine phenotype of ECE20 knock-out mice supports the secondary incorporation of ECE18 into the regulation of this trait in primates. Our findings reveal that the mammalian En1 regulatory machinery diversified to incorporate both shared and lineage-restricted enhancers to regulate the same phenotype, and also have implications for understanding the forces that shape the robustness and evolvability of developmental traits.


Assuntos
Genes Homeobox , Proteínas de Homeodomínio , Camundongos , Animais , Humanos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Sequências Reguladoras de Ácido Nucleico , Camundongos Knockout , Fenótipo , Glândulas Sudoríparas/metabolismo , Mamíferos/genética , Mamíferos/metabolismo
3.
J Invest Dermatol ; 143(8): 1529-1537.e2, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36804570

RESUMO

XEDAR is a member of the TNF receptor subfamily and a mediator of the ectodysplasin (EDA) pathway. EDA signaling plays evolutionarily conserved roles in the development of the ectodermal appendage organ class, which includes hair, eccrine sweat glands, and mammary glands. Loss-of-function sequence variants of EDA, which encodes the two major ligand isoforms, EDA-A1 and EDA-A2, result in X-linked hypohidrotic ectodermal dysplasia characterized by defects in two or more types of ectodermal appendages. EDA-A1 and EDA-A2 signal through the receptors EDAR and XEDAR, respectively. Although the contributions of the EDA-A1/EDAR signaling pathway to EDA-dependent ectodermal appendage phenotypes have been extensively characterized, the significance of the EDA-A2/XEDAR branch of the pathway has remained obscure. In this study, we report the phenotypic consequences of disrupting the EDA-A2/XEDAR pathway on mammary gland differentiation and growth. Using a mouse Xedar knockout model, we show that Xedar has a specific and temporally restricted role in promoting late pubertal growth and branching of the mammary epithelium that can be influenced by genetic background. Our findings implicate Xedar in ectodermal appendage development and suggest that the EDA-A2/XEDAR signaling axis contributes to the etiology of EDA-dependent mammary phenotypes.


Assuntos
Ectodisplasinas , Proteínas de Membrana , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Proteínas de Membrana/genética , Morfogênese , Receptores do Fator de Necrose Tumoral , Transdução de Sinais , Animais , Camundongos
5.
Proc Natl Acad Sci U S A ; 118(16)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33850016

RESUMO

Humans sweat to cool their bodies and have by far the highest eccrine sweat gland density among primates. Humans' high eccrine gland density has long been recognized as a hallmark human evolutionary adaptation, but its genetic basis has been unknown. In humans, expression of the Engrailed 1 (EN1) transcription factor correlates with the onset of eccrine gland formation. In mice, regulation of ectodermal En1 expression is a major determinant of natural variation in eccrine gland density between strains, and increased En1 expression promotes the specification of more eccrine glands. Here, we show that regulation of EN1 has evolved specifically on the human lineage to promote eccrine gland formation. Using comparative genomics and validation of ectodermal enhancer activity in mice, we identified a human EN1 skin enhancer, hECE18. We showed that multiple epistatically interacting derived substitutions in the human ECE18 enhancer increased its activity compared with nonhuman ape orthologs in cultured keratinocytes. Repression of hECE18 in human cultured keratinocytes specifically attenuated EN1 expression, indicating this element positively regulates EN1 in this context. In a humanized enhancer knock-in mouse, hECE18 increased developmental En1 expression in the skin to induce the formation of more eccrine glands. Our study uncovers a genetic basis contributing to the evolution of one of the most singular human adaptations and implicates multiple interacting mutations in a single enhancer as a mechanism for human evolutionary change.


Assuntos
Regulação da Temperatura Corporal/genética , Regulação da Temperatura Corporal/fisiologia , Proteínas de Homeodomínio/genética , Animais , Evolução Biológica , Glândulas Écrinas/metabolismo , Glândulas Écrinas/fisiologia , Ectoderma , Elementos Facilitadores Genéticos/genética , Evolução Molecular , Proteínas de Homeodomínio/metabolismo , Humanos , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Sequências Reguladoras de Ácido Nucleico/genética , Pele/metabolismo , Sudorese/genética , Sudorese/fisiologia , Fatores de Transcrição/genética
7.
J Hum Evol ; 125: 99-105, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30502901

RESUMO

Humans differ in many respects from other primates, but perhaps no derived human feature is more striking than our naked skin. Long purported to be adaptive, humans' unique external appearance is characterized by changes in both the patterning of hair follicles and eccrine sweat glands, producing decreased hair cover and increased sweat gland density. Despite the conspicuousness of these features and their potential evolutionary importance, there is a lack of clarity regarding how they evolved within the primate lineage. We thus collected and quantified the density of hair follicles and eccrine sweat glands from five regions of the skin in three species of primates: macaque, chimpanzee and human. Although human hair cover is greatly attenuated relative to that of our close relatives, we find that humans have a chimpanzee-like hair density that is significantly lower than that of macaques. In contrast, eccrine gland density is on average 10-fold higher in humans compared to chimpanzees and macaques, whose density is strikingly similar. Our findings suggest that a decrease in hair density in the ancestors of humans and apes was followed by an increase in eccrine gland density and a reduction in fur cover in humans. This work answers long-standing questions about the traits that make human skin unique and substantiates a model in which the evolution of expanded eccrine gland density was exclusive to the human lineage.


Assuntos
Glândulas Écrinas/fisiologia , Folículo Piloso/fisiologia , Macaca mulatta/fisiologia , Pan troglodytes/fisiologia , Animais , Evolução Biológica , Humanos
8.
Proc Natl Acad Sci U S A ; 112(32): 9932-7, 2015 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-26195765

RESUMO

Among the unique features of humans, one of the most salient is the ability to effectively cool the body during extreme prolonged activity through the evapotranspiration of water on the skin's surface. The evolution of this novel physiological ability required a dramatic increase in the density and distribution of eccrine sweat glands relative to other mammals and a concomitant reduction of body hair cover. Elucidation of the genetic underpinnings for these adaptive changes is confounded by a lack of knowledge about how eccrine gland fate and density are specified during development. Moreover, although reciprocal changes in hair cover and eccrine gland density are required for efficient thermoregulation, it is unclear if these changes are linked by a common genetic regulation. To identify pathways controlling the relative patterning of eccrine glands and hair follicles, we exploited natural variation in the density of these organs between different strains of mice. Quantitative trait locus mapping identified a large region on mouse Chromosome 1 that controls both hair and eccrine gland densities. Differential and allelic expression analysis of the genes within this interval coupled with subsequent functional studies demonstrated that the level of En1 activity directs the relative numbers of eccrine glands and hair follicles. These findings implicate En1 as a newly identified and reciprocal determinant of hair follicle and eccrine gland density and identify a pathway that could have contributed to the evolution of the unique features of human skin.


Assuntos
Glândulas Écrinas/metabolismo , Variação Genética , Folículo Piloso/metabolismo , Animais , Mapeamento Cromossômico , Cromossomos de Mamíferos/genética , Cruzamentos Genéticos , Ectoderma/metabolismo , Feminino , Regulação da Expressão Gênica , Genoma , Masculino , Camundongos Endogâmicos C57BL , Herança Multifatorial/genética , Locos de Características Quantitativas/genética , Característica Quantitativa Herdável , Especificidade da Espécie
9.
Cell ; 152(4): 691-702, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23415220

RESUMO

An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.


Assuntos
Evolução Biológica , Receptor Edar/genética , Glândulas Exócrinas/fisiologia , Cabelo/fisiologia , Camundongos , Modelos Animais , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Evolução Molecular , Técnicas de Introdução de Genes , Pleiotropia Genética , Haplótipos , Humanos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Couro Cabeludo/fisiologia , Alinhamento de Sequência , Adulto Jovem
10.
BMC Res Notes ; 4: 381, 2011 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-21974968

RESUMO

BACKGROUND: The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFß signaling and activation of the amino acid restriction response (AAR) have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type. RESULTS: We report that HF modulation of the expression of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFß signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR). CONCLUSIONS: Our findings suggest activation of the ISR may be a common mechanism underlying HF biological effects.

11.
Dev Cell ; 2(4): 437-48, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11970894

RESUMO

Cell motility is regulated by extracellular cues and by intracellular factors that accumulate at sites of contact between cells and the extracellular matrix. One of these factors, focal adhesion kinase (FAK), regulates the cycle of focal adhesion formation and disassembly that is required for cell movement to occur. Recently, Wnt signaling has also been implicated in the control of cell movement in vertebrates, but the mechanism through which Wnt proteins influence motility is unclear. We demonstrate that Drosphila Wnt4 is required for cell movement and FAK regulation during ovarian morphogenesis. Dfrizzled2, Disheveled, and protein kinase C are also required. The DWnt4 cell motility pathway is distinct from both the canonical Wnt pathway and the planar polarity pathway. Our data suggest that DWnt4 facilitates motility through regulation of focal adhesions.


Assuntos
Movimento Celular/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Glicoproteínas/metabolismo , Ovário/citologia , Proteínas Tirosina Quinases/metabolismo , Animais , Polaridade Celular/fisiologia , Drosophila/crescimento & desenvolvimento , Proteínas de Drosophila/genética , Células Epiteliais/citologia , Feminino , Proteína-Tirosina Quinases de Adesão Focal , Regulação da Expressão Gênica no Desenvolvimento , Glicoproteínas/genética , Mutação/fisiologia , Ovário/crescimento & desenvolvimento , Transdução de Sinais/fisiologia , Proteínas Wnt
12.
Cancer Res ; 62(1): 277-82, 2002 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11782388

RESUMO

beta-Catenin plays an important role in signal transduction pathways that regulate cellular differentiation and proliferation. The increased concentration of this protein in the cytoplasm favors its binding to the T-cell factor (TCF) family of DNA-binding proteins, and it subsequently translocates to the nucleus, where it induces transcription of specific genes. We explored mechanisms that lead to activation of beta-catenin/TCF-dependent transcription in esophageal squamous cell carcinoma (ESCC) independent of adenomatous polyposis coli and beta-catenin mutation. Electrophoresis mobility shift assay demonstrated that TCF4 and beta-catenin form a complex and have DNA binding activity. However, there was no constitutive activation of beta-catenin/TCF-dependent transcription. Coculture experiments demonstrated that Wnt-1, but not Wnt-5A and Wnt-7A, activated the TCF reporter gene. Additionally, when cultured with Wnt-1-conditioned media, ESCC cell lines showed an accumulation of beta-catenin in the cytoplasm. Although both Wnt and epidermal growth factor inactivate glycogen synthase kinase 3beta, activation of epidermal growth factor receptor did not stabilize beta-catenin. A comparison of extracellular stimuli suggests that specific Wnt family members stabilize beta-catenin with resulting activation of TCF-dependent transcription in ESCC.


Assuntos
Proteínas do Citoesqueleto/fisiologia , Fator de Crescimento Epidérmico/fisiologia , Neoplasias Esofágicas/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Transativadores , Fatores de Transcrição/fisiologia , Proteínas de Peixe-Zebra , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Citoplasma/metabolismo , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Receptores ErbB/fisiologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase , Quinases da Glicogênio Sintase , Humanos , Transdução de Sinais , Fatores de Transcrição TCF , Proteína 2 Semelhante ao Fator 7 de Transcrição , Ativação Transcricional/fisiologia , Transfecção , Células Tumorais Cultivadas , Proteínas Wnt , Proteína Wnt1 , Proteínas de Xenopus , Xenopus laevis , beta Catenina
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