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1.
Gene ; 731: 144338, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31923576

RESUMO

The primary feather follicles are universal skin appendages widely distributed in the skin of feathered birds. The morphogenesis and development of the primary feather follicles in goose skin remain largely unknown. Here, the induction of primary feather follicles in goose embryonic skin (pre-induction vs induction) was investigated by de novo transcriptome analyses to reveal 409 differentially expressed genes (DEGs). The DEGs were characterized to potentially regulate the de novo formation of feather follicle primordia consisting of placode (4 genes) and dermal condensate (12 genes), and the thickening of epidermis (5 genes) and dermal fibroblasts (17 genes), respectively. Further analyses enriched DEGs into GO terms represented as cell adhesion and KEGG pathways including Wnt and Hedgehog signaling pathways that are highly correlated with cell communication and molecular regulation. Six selected Wnt pathway genes were detected by qPCR with up-regulation in goose skin during the induction of primary feather follicles. The localization of WNT16, SFRP1 and FRZB by in situ hybridization showed weak expression in the primary feather primordia, whereas FZD1, LEF1 and DKK1 were expressed initially in the inter-follicular skin and feather follicle primordia, then mainly restricted in the feather primordia. The spatial-temporal expression patterns indicate that Wnt pathway genes DKK1, FZD1 and LEF1 are the important regulators functioned in the induction of primary feather follicle in goose skin. The dynamic molecular changes and specific gene expression patterns revealed in this report provide the general knowledge of primary feather follicle and skin development in waterfowl, and contribute to further understand the diversity of hair and feather development beyond the mouse and chicken models.


Assuntos
Plumas/embriologia , Gansos , Genes Controladores do Desenvolvimento , Folículo Piloso/embriologia , Morfogênese/genética , Pele/embriologia , Animais , Embrião de Galinha , Embrião não Mamífero , Desenvolvimento Embrionário/genética , Plumas/metabolismo , Gansos/embriologia , Gansos/genética , Gansos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Genes Controladores do Desenvolvimento/genética , Folículo Piloso/metabolismo , Pele/metabolismo
2.
Biochem Biophys Res Commun ; 509(4): 862-868, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30638933

RESUMO

Sox13, a group D member of the Sry-related high-mobility group box (Sox) transcription factor family, is expressed in various tissues including the hair follicle. However, its spatiotemporal expression patterns in the hair follicle and its role in hair development remain to be elucidated. To address these questions, we generated Sox13-LacZ-knock-in mice (Sox13LacZ/+), in which the LacZ reporter gene was inserted in-frame into exon 2, which contains the translation initiation codon. X-gal staining in Sox13LacZ/+ embryos revealed that Sox13 is initially expressed in the epithelial portion of the placode, and subsequently in the hair germ and the hair peg during early hair follicle development. In postnatal catagen and anagen, Sox13 was detected in the epithelial sheath, whereas in telogen, Sox13 was localized in the bulge region, where hair follicle stem cells reside. Immunohistochemistry with an anti-ß-galactosidase antibody and anti-hair keratin antibodies that specifically mark the different layers of the hair follicle revealed that Sox13 was predominantly expressed in the outer root sheath in anagen. However, the integumentary structures of Sox13LacZ/LacZ mice were grossly and histologically indistinguishable from those of wild type mice. These results suggest that although Sox13 is dispensable for epidermal and adnexal development, Sox13 is a useful marker for early hair follicle development.


Assuntos
Autoantígenos/genética , Regulação da Expressão Gênica no Desenvolvimento , Folículo Piloso/crescimento & desenvolvimento , Análise Espaço-Temporal , Animais , Autoantígenos/análise , Biomarcadores , Conexinas , Embrião de Mamíferos , Folículo Piloso/embriologia , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra
3.
Dev Cell ; 48(1): 32-48.e5, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30595537

RESUMO

Cell fate transitions are essential for specification of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we identify, with 3D and 4D microscopy, unclustered precursors of dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes. With population-based and single-cell transcriptomics, we define a molecular time-lapse from pre-DC fate specification through DC niche formation and establish the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then coincide with DC formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for pre-DC specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.


Assuntos
Diferenciação Celular/fisiologia , Derme/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Folículo Piloso/metabolismo , Animais , Fibroblastos/citologia , Folículo Piloso/embriologia , Transdução de Sinais/genética , Pele/metabolismo , Células-Tronco/citologia
4.
Nat Commun ; 9(1): 2333, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899403

RESUMO

Merkel cells are innervated mechanosensory cells responsible for light-touch sensations. In murine dorsal skin, Merkel cells are located in touch domes and found in the epidermis around primary hairs. While it has been shown that Merkel cells are skin epithelial cells, the progenitor cell population that gives rise to these cells is unknown. Here, we show that during embryogenesis, SOX9-positive (+) cells inside hair follicles, which were previously known to give rise to hair follicle stem cells (HFSCs) and cells of the hair follicle lineage, can also give rise to Merkel Cells. Interestingly, while SOX9 is critical for HFSC specification, it is dispensable for Merkel cell formation. Conversely, FGFR2 is required for Merkel cell formation but is dispensable for HFSCs. Together, our studies uncover SOX9(+) cells as precursors of Merkel cells and show the requirement for FGFR2-mediated epithelial signalling in Merkel cell specification.


Assuntos
Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Folículo Piloso/embriologia , Folículo Piloso/metabolismo , Células de Merkel/citologia , Células de Merkel/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição SOX9/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem da Célula , Feminino , Técnicas de Inativação de Genes , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Folículo Piloso/citologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Biológicos , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Gravidez , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Fatores de Transcrição SOX9/antagonistas & inibidores , Fatores de Transcrição SOX9/genética , Transdução de Sinais , Fatores de Transcrição/metabolismo
5.
Nat Cell Biol ; 20(5): 541-552, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29662173

RESUMO

Organ morphogenesis is a complex process coordinated by cell specification, epithelial-mesenchymal interactions and tissue polarity. A striking example is the pattern of regularly spaced, globally aligned mammalian hair follicles, which emerges through epidermal-dermal signaling and planar polarized morphogenesis. Here, using live-imaging, we discover that developing hair follicles polarize through dramatic cell rearrangements organized in a counter-rotational pattern of cell flows. Upon hair placode induction, Shh signaling specifies a radial pattern of progenitor fates that, together with planar cell polarity, induce counter-rotational rearrangements through myosin and ROCK-dependent polarized neighbour exchanges. Importantly, these cell rearrangements also establish cell fate asymmetry by repositioning radial progenitors along the anterior-posterior axis. These movements concurrently displace associated mesenchymal cells, which then signal asymmetrically to maintain polarized cell fates. Our results demonstrate how spatial patterning and tissue polarity generate an unexpected collective cell behaviour that in turn, establishes both morphological and cell fate asymmetry.


Assuntos
Diferenciação Celular , Linhagem da Célula , Movimento Celular , Polaridade Celular , Forma Celular , Folículo Piloso/fisiologia , Morfogênese , Células-Tronco/fisiologia , Animais , Comunicação Celular , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Feminino , Idade Gestacional , Folículo Piloso/embriologia , Folículo Piloso/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Masculino , Mecanotransdução Celular , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos Endogâmicos C57BL , Miosina Tipo II/genética , Miosina Tipo II/metabolismo , Células-Tronco/metabolismo , Fatores de Tempo , Técnicas de Cultura de Tecidos , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
6.
Cell Rep ; 22(1): 242-254, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29298425

RESUMO

The mammalian hair follicle arises during embryonic development from coordinated interactions between the epidermis and dermis. It is currently unclear how to recapitulate hair follicle induction in pluripotent stem cell cultures for use in basic research studies or in vitro drug testing. To date, generation of hair follicles in vitro has only been possible using primary cells isolated from embryonic skin, cultured alone or in a co-culture with stem cell-derived cells, combined with in vivo transplantation. Here, we describe the derivation of skin organoids, constituting epidermal and dermal layers, from a homogeneous population of mouse pluripotent stem cells in a 3D culture. We show that skin organoids spontaneously produce de novo hair follicles in a process that mimics normal embryonic hair folliculogenesis. This in vitro model of skin development will be useful for studying mechanisms of hair follicle induction, evaluating hair growth or inhibitory drugs, and modeling skin diseases.


Assuntos
Embrião de Mamíferos , Folículo Piloso , Células-Tronco Pluripotentes Induzidas , Organoides , Animais , Técnicas de Cultura de Células , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Folículo Piloso/citologia , Folículo Piloso/embriologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Organoides/citologia , Organoides/embriologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-28246184

RESUMO

Epithelia exist in the animal body since the onset of embryonic development; they generate tissue barriers and specify organs and glands. Through epithelial-mesenchymal transitions (EMTs), epithelia generate mesenchymal cells that form new tissues and promote healing or disease manifestation when epithelial homeostasis is challenged physiologically or pathologically. Transforming growth factor-ßs (TGF-ßs), activins, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs) have been implicated in the regulation of epithelial differentiation. These TGF-ß family ligands are expressed and secreted at sites where the epithelium interacts with the mesenchyme and provide paracrine queues from the mesenchyme to the neighboring epithelium, helping the specification of differentiated epithelial cell types within an organ. TGF-ß ligands signal via Smads and cooperating kinase pathways and control the expression or activities of key transcription factors that promote either epithelial differentiation or mesenchymal transitions. In this review, we discuss evidence that illustrates how TGF-ß family ligands contribute to epithelial differentiation and induce mesenchymal transitions, by focusing on the embryonic ectoderm and tissues that form the external mammalian body lining.


Assuntos
Transição Epitelial-Mesenquimal , Epitélio/embriologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Diferenciação Celular , Epiderme/embriologia , Plumas/embriologia , Folículo Piloso/embriologia , Humanos , Mesoderma/citologia , Crista Neural/citologia , Dente/embriologia
8.
PLoS Biol ; 15(7): e2002117, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28700594

RESUMO

Two theories address the origin of repeating patterns, such as hair follicles, limb digits, and intestinal villi, during development. The Turing reaction-diffusion system posits that interacting diffusible signals produced by static cells first define a prepattern that then induces cell rearrangements to produce an anatomical structure. The second theory, that of mesenchymal self-organisation, proposes that mobile cells can form periodic patterns of cell aggregates directly, without reference to any prepattern. Early hair follicle development is characterised by the rapid appearance of periodic arrangements of altered gene expression in the epidermis and prominent clustering of the adjacent dermal mesenchymal cells. We assess the contributions and interplay between reaction-diffusion and mesenchymal self-organisation processes in hair follicle patterning, identifying a network of fibroblast growth factor (FGF), wingless-related integration site (WNT), and bone morphogenetic protein (BMP) signalling interactions capable of spontaneously producing a periodic pattern. Using time-lapse imaging, we find that mesenchymal cell condensation at hair follicles is locally directed by an epidermal prepattern. However, imposing this prepattern's condition of high FGF and low BMP activity across the entire skin reveals a latent dermal capacity to undergo spatially patterned self-organisation in the absence of epithelial direction. This mesenchymal self-organisation relies on restricted transforming growth factor (TGF) ß signalling, which serves to drive chemotactic mesenchymal patterning when reaction-diffusion patterning is suppressed, but, in normal conditions, facilitates cell movement to locally prepatterned sources of FGF. This work illustrates a hierarchy of periodic patterning modes operating in organogenesis.


Assuntos
Folículo Piloso/embriologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Padronização Corporal , Diferenciação Celular , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos , Transdução de Sinais , Pele/citologia , Pele/embriologia , Pele/metabolismo , Fator de Crescimento Transformador beta/metabolismo
9.
Dev Biol ; 428(1): 188-203, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28599846

RESUMO

Hair follicles of the mammalian epidermis display local order and global alignment, a complex pattern instructed by the core planar cell polarity (PCP) pathway. Here we address the contributions of core PCP genes, Van Gogh-like and Frizzled, to the establishment, local refinement, and global order of embryonic and postnatal hair follicles. We find that, similar to Fz6 mutants, the disordered hair patterns of Vangl2 mutants are refined over time and eventually corrected. In both mutants, we find that tissue-level reorientation occurs through locally coordinated follicle rotation at stereotyped locations. Strikingly, Vangl2 and Fz6 mutant follicles collectively rotate with opposing directionalities, suggesting that redundant core PCP signals contribute to their directed realignment. Consistently, global follicle alignment is not restored upon conditional ablation of both Vangl1 and Vangl2 genes. Instead, spatially distinct patterns of whorls and crosses emerge and persist even after a complete cycle of hair follicle regeneration. Thus, local refinement of hair follicles into higher order patterns can occur independently of the core PCP system, however, their global alignment with the body axes requires PCP function throughout morphogenesis, growth and regeneration.


Assuntos
Padronização Corporal/genética , Polaridade Celular/genética , Receptores Frizzled/genética , Folículo Piloso/embriologia , Proteínas do Tecido Nervoso/genética , Animais , Padronização Corporal/fisiologia , Proteínas de Transporte/genética , Folículo Piloso/citologia , Folículo Piloso/fisiologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Morfogênese/genética , Transdução de Sinais/genética
10.
Br J Dermatol ; 177(6): 1485-1494, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28626889

RESUMO

The deciphering of the hedgehog (Hh) signalling pathway implicated in the tumorigenesis of basal cell carcinoma (BCC) led to the development of targeted drug therapies, the Hh pathway inhibitors (HPIs) vismodegib and sonidegib. In the skin, physiological Hh signalling is activated in growing hair follicles (HFs), where it is required for proliferation of the epithelium of HFs during morphogenesis and for their postnatal growth. The effects of HPI treatment leading to the regression of BCC and the development of alopecia underpin the central role of the Hh pathway in BCC formation, as well as hair cycling. Given the fact that BCC is a follicular-driven tumour, it is a fine tuning of events that regulate hair cycling that may drive towards the formation of benign follicular hamartomas or malignant BCC neoplasms. Wnt/ß-catenin signalling interacts with the Hh signalling during HF morphogenesis, normal hair cycling and BCC development. The aim of this review is to present how key molecular events implicated in Hh pathway crosstalk in the HF are also involved in BCC pathogenesis and result in the alopecia developed by HPI treatment.


Assuntos
Alopecia/induzido quimicamente , Carcinoma Basocelular/patologia , Proteínas Hedgehog/antagonistas & inibidores , Neoplasias Cutâneas/patologia , Carcinogênese/patologia , Folículo Piloso/embriologia , Folículo Piloso/crescimento & desenvolvimento , Proteínas Hedgehog/farmacologia , Humanos , Morfogênese/fisiologia , Transdução de Sinais/fisiologia , beta Catenina/metabolismo
11.
Development ; 144(10): 1887-1895, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28512199

RESUMO

SOX family proteins SOX2 and SOX18 have been reported as being essential in determining hair follicle type; however, the role they play during development remains unclear. Here, we demonstrate that Sox18 regulates the normal differentiation of the dermal papilla of all hair types. In guard (primary) hair dermal condensate (DC) cells, we identified transient Sox18 in addition to SOX2 expression at E14.5, which allowed fate tracing of primary DC cells until birth. Similarly, expression of Sox18 was detected in the DC cells of secondary hairs at E16.5 and in tertiary hair at E18.5. Dominant-negative Sox18 mutation (opposum) did not prevent DC formation in any hair type. However, it affected dermal papilla differentiation, restricting hair formation especially in secondary and tertiary hairs. This Sox18 mutation also prevented neonatal dermal cells or dermal papilla spheres from inducing hair in regeneration assays. Microarray expression studies identified WNT5A and TNC as potential downstream effectors of SOX18 that are important for epidermal WNT signalling. In conclusion, SOX18 acts as a mesenchymal molecular switch necessary for the formation and function of the dermal papilla in all hair types.


Assuntos
Diferenciação Celular/genética , Folículo Piloso/embriologia , Cabelo/embriologia , Fatores de Transcrição SOXF/fisiologia , Animais , Derme/embriologia , Derme/metabolismo , Embrião de Mamíferos , Células Epidérmicas , Epiderme/embriologia , Feminino , Genes Dominantes , Genes de Troca/fisiologia , Cabelo/metabolismo , Folículo Piloso/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fatores de Transcrição SOXF/genética
12.
J Dermatol ; 44(3): 259-278, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28256760

RESUMO

Numerous benign and occasionally malignant tumors arise from the folliculosebaceous apparatus. Confusing terminology, rarity of malignant variants and overlapping histological features can lead to diagnostic uncertainty. This review highlights the clinical and histopathological features that help to classify these entities, as well as the various syndromes associated with certain members of this large family of tumors.


Assuntos
Doenças do Cabelo/patologia , Folículo Piloso/patologia , Glândulas Sebáceas/patologia , Neoplasias Cutâneas/patologia , Doenças do Cabelo/diagnóstico , Folículo Piloso/anatomia & histologia , Folículo Piloso/embriologia , Humanos , Neoplasias das Glândulas Sebáceas/diagnóstico , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias Cutâneas/diagnóstico
13.
Science ; 354(6319)2016 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-28008008

RESUMO

The gain of eccrine sweat glands in hairy body skin has empowered humans to run marathons and tolerate temperature extremes. Epithelial-mesenchymal cross-talk is integral to the diverse patterning of skin appendages, but the molecular events underlying their specification remain largely unknown. Using genome-wide analyses and functional studies, we show that sweat glands are specified by mesenchymal-derived bone morphogenetic proteins (BMPs) and fibroblast growth factors that signal to epithelial buds and suppress epithelial-derived sonic hedgehog (SHH) production. Conversely, hair follicles are specified when mesenchymal BMP signaling is blocked, permitting SHH production. Fate determination is confined to a critical developmental window and is regionally specified in mice. In contrast, a shift from hair to gland fates is achieved in humans when a spike in BMP silences SHH during the final embryonic wave(s) of bud morphogenesis.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Glândulas Écrinas/embriologia , Folículo Piloso/embriologia , Proteínas Hedgehog/metabolismo , Mesoderma/embriologia , Suor , Animais , Glândulas Écrinas/metabolismo , Epitélio/embriologia , Epitélio/metabolismo , Humanos , Mesoderma/metabolismo , Camundongos , Morfogênese , Transdução de Sinais , Via de Sinalização Wnt
15.
Genes Dev ; 30(20): 2325-2338, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27807033

RESUMO

Growth and regeneration of one tissue within an organ compels accommodative changes in the surrounding tissues. However, the molecular nature and operating logic governing these concurrent changes remain poorly defined. The dermal adipose layer expands concomitantly with hair follicle downgrowth, providing a paradigm for studying coordinated changes of surrounding lineages with a regenerating tissue. Here, we discover that hair follicle transit-amplifying cells (HF-TACs) play an essential role in orchestrating dermal adipogenesis through secreting Sonic Hedgehog (SHH). Depletion of Shh from HF-TACs abrogates both dermal adipogenesis and hair follicle growth. Using cell type-specific deletion of Smo, a gene required in SHH-receiving cells, we found that SHH does not act on hair follicles, adipocytes, endothelial cells, and hematopoietic cells for adipogenesis. Instead, SHH acts directly on adipocyte precursors, promoting their proliferation and their expression of a key adipogenic gene, peroxisome proliferator-activated receptor γ (Pparg), to induce dermal adipogenesis. Our study therefore uncovers a critical role for TACs in orchestrating the generation of both their own progeny and a neighboring lineage to achieve concomitant tissue production across lineages.


Assuntos
Adipogenia/fisiologia , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Proteínas Hedgehog/metabolismo , Pele/metabolismo , Adipogenia/genética , Animais , Proliferação de Células/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Folículo Piloso/embriologia , Folículo Piloso/crescimento & desenvolvimento , Masculino , Camundongos , Transdução de Sinais , Pele/embriologia , Pele/crescimento & desenvolvimento
16.
PLoS Genet ; 12(7): e1006150, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27414798

RESUMO

The Sonic hedgehog (Shh) signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance.


Assuntos
Ectodisplasinas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/metabolismo , Células de Merkel/citologia , Proteína Wnt1/metabolismo , Animais , Linhagem da Célula , Reparo do DNA , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Deleção de Genes , Genótipo , Folículo Piloso/embriologia , Folículo Piloso/metabolismo , Homeostase , Ligantes , Masculino , Camundongos , Microscopia de Fluorescência , Morfogênese , Mutação , Neurônios/metabolismo , Transdução de Sinais , Pele/embriologia , Pele/metabolismo , Tato
17.
PLoS Genet ; 12(7): e1006151, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27414999

RESUMO

An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures.


Assuntos
Proteínas Hedgehog/fisiologia , Células de Merkel/citologia , Complexo Repressor Polycomb 2/fisiologia , Transdução de Sinais , Pele/embriologia , Animais , Linhagem da Célula , Proliferação de Células , Epiderme/embriologia , Epiderme/metabolismo , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Folículo Piloso/embriologia , Queratinócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Pele/metabolismo , Células-Tronco/citologia , Transcrição Genética
18.
Development ; 143(15): 2803-17, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27317810

RESUMO

Oral epithelia protect against constant challenges by bacteria, viruses, toxins and injury while also contributing to the formation of ectodermal appendages such as teeth, salivary glands and lingual papillae. Despite increasing evidence that differentiation pathway genes are frequently mutated in oral cancers, comparatively little is known about the mechanisms that regulate normal oral epithelial development. Here, we characterize oral epithelial stratification and describe multiple distinct functions for the mitotic spindle orientation gene LGN (Gpsm2) in promoting differentiation and tissue patterning in the mouse oral cavity. Similar to its function in epidermis, apically localized LGN directs perpendicular divisions that promote stratification of the palatal, buccogingival and ventral tongue epithelia. Surprisingly, however, in dorsal tongue LGN is predominantly localized basally, circumferentially or bilaterally and promotes planar divisions. Loss of LGN disrupts the organization and morphogenesis of filiform papillae but appears to be dispensable for embryonic hair follicle development. Thus, LGN has crucial tissue-specific functions in patterning surface ectoderm and its appendages by controlling division orientation.


Assuntos
Proteínas de Transporte/metabolismo , Epitélio/metabolismo , Folículo Piloso/embriologia , Folículo Piloso/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Ciclo Celular , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Imuno-Histoquímica , Camundongos , Microscopia Eletrônica de Varredura , Morfogênese/genética , Morfogênese/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Papilas Gustativas/embriologia , Papilas Gustativas/metabolismo , Língua/embriologia , Língua/metabolismo
19.
Matrix Biol ; 56: 42-56, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27234308

RESUMO

Laminins are the most abundant non-collagenous basement membrane (BM) components, composed of an α, ß and γ chain. The laminin γ1 chain, encoded by LAMC1, is the most abundant γ chain. The main laminin isoforms in the dermo-epidermal junction (DEJ) are laminin-332, laminin-511 and laminin-211, the latter being restricted to the lower part of hair follicles (HFs). Complete deletion of LAMC1 results in lethality around embryonic day 5.5. To study the function of laminin γ1 containing isoforms in skin development and maturation after birth, we generated mice lacking LAMC1 expression in basal keratinocytes (LAMC1EKO) using the keratin 14 (K14) Cre/loxP system. This deletion resulted in loss of keratinocyte derived laminin-511 and in deposition of fibroblast derived laminin-211 throughout the whole DEJ. The DEJ in areas between hemidesmosomes was thickened, whereas hemidesmosome morphology was normal. Most strikingly, LAMC1EKO mice showed delayed HF morphogenesis accompanied by reduced proliferation of hair matrix cells and impaired differentiation of hair shafts (HS). However, this deletion did not interfere with early HF development, since placode numbers and embryonic hair germ formation were not affected. Microarray analysis of skin revealed down regulation of mainly different hair keratins. This is due to reduced expression of transcription factors such as HoxC13, FoxN1, FoxQ1 and Msx2, known to regulate expression of hair keratins. While the role of laminin-511 in signaling during early hair germ formation and elongation phase has been described, we here demonstrate that epidermal laminin-511 is also a key regulator for later hair development and HS differentiation.


Assuntos
Folículo Piloso/crescimento & desenvolvimento , Laminina/genética , Animais , Membrana Basal/metabolismo , Diferenciação Celular , Células Cultivadas , Deleção de Genes , Expressão Gênica , Folículo Piloso/citologia , Folículo Piloso/embriologia , Queratinócitos/metabolismo , Laminina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese
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