Involvement of Wnt, Eda and Shh at defined stages of sweat gland development

Cui, Chang‐Yi; Yin, Mingzhu; Sima, Jian; Childress, Victoria; Michel, Mary Ellen; Piao, Yulan; Schlessinger, David

doi:10.1242/dev.109231

Cited by 60 publications

(81 citation statements)

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“…Other genes in the Wnt signaling pathway showed no appreciable change in expression (Table S1). Dkk4, Wnt10b and Fzd10, which had previously been suggested as potential targets of Eda activation in skin appendages (Cui et al, 2014;Fliniaux et al, 2008;Voutilainen et al, 2012;Zhang et al, 2009), were comparably downregulated in Tabby MGs. Of particular interest, the Dkk4 receptor Lrp6, newly identified here as an Eda target, was reduced by 44% at E14.5 and 32% at E15.5 in Tabby eyelids.…”

Section: Dkk4 and Other Wnt Pathway Components Are Induced By Eda Durmentioning

confidence: 72%

“…Eyelids for study and livers to provide DNA for genotyping were excised under dissection microscopy and were fixed, cultured or stored at 80°C until use. Genotyping for Dkk4Tg and Tabby was performed as previously described (Cui et al, 2014).…”

Section: Mouse Models Timed Mating and Genotypingmentioning

confidence: 99%

“…For in situ hybridization, 20 µm frozen sections were fixed in 4% paraformaldehyde as described previously (Cui et al, 2014). All probe cDNAs were amplified by PCR and subcloned into a pGEM-T vector (Promega).…”

Section: Histology Immunohistochemistry and In Situ Hybridizationmentioning

confidence: 99%

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Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development

Sima¹,

Piao²,

Chen³

et al. 2016

Development

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Secreted Dickkopf (Dkk) proteins are major Wnt pathway modulators during organ development. Dkk1 has been widely studied and acts as a general Wnt inhibitor. However, the molecular function of other Dkks remains largely unknown. Here, we show that Dkk4 selectively inhibits a subset of Wnts, but is further inactivated by proteolytic cleavage. Meibomian gland (MG) formation is employed as a model where Dkk4 and its Wnt targets are expressed. Skin-specific expression of Dkk4 arrests MG growth at early germ phase, which is similar to that observed in Eda-ablated Tabby mice. Consistent with transient Dkk4 action, intact Dkk4 inhibits MG extension but the cleaved form progressively increases during MG development with a concomitant upswing in Wnt activity. Furthermore, both Dkk4 and its receptor (and Wnt co-receptor) Lrp6 are direct Eda targets during MG induction. In cell and organotypic cultures, Dkk4 inhibition is eliminated by elevation of Lrp6. Also, Lrp6 upregulation restores MG formation in Tabby mice. Thus, the dynamic state of Dkk4 itself and its interaction with Lrp6 modulates Wnt function during MG development, with a novel limitation of Dkk4 action by proteolytic cleavage.

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Section: Dkk4 and Other Wnt Pathway Components Are Induced By Eda Durmentioning

confidence: 72%

Section: Mouse Models Timed Mating and Genotypingmentioning

confidence: 99%

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Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development

Sima¹,

Piao²,

Chen³

et al. 2016

Development

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“…Work in model systems, particularly the mouse, as well as the mapping of causal genetic mutations underlying clinical cases of ectodermal dysplasia in humans have implicated a number of common molecular pathways as critical in the formation of both eccrine glands and hair follicles. These include the canonical Wnt, BMP, Ectodysplasin, and Shh pathways (7)(8)(9). However, the molecular program that specifically leads to the formation of eccrine glands as opposed to hair follicles and the distinct mechanisms that govern eccrine gland patterning are poorly understood.…”

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confidence: 99%

A genetic basis of variation in eccrine sweat gland and hair follicle density

Kamberov

Karlsson

Kamberova

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.eccrine sweat gland | hair follicle | ectodermal placode | engrailed 1 | ectodermal appendage

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“…Indeed, epidermal-specific loss of β-catenin abrogated sweat bud formation ( fig. S2A) (18). Cross-talk at the epidermal-dermal border involving Wnt signaling is also well established (19).…”

Section: Bmp Signaling Enhances Mesenchymal But Dampens Epithelial Wnmentioning

confidence: 99%

839 Spatiotemporal antagonism in mesenchymal-epithelial Signaling in sweat versus hair fate decision

Polak

Keyes

et al. 2017

Journal of Investigative Dermatology

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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.Epithelial appendages-including hair follicles (HFs) and teeth as well as mammary, sweat, and salivary glands-begin to form during embryogenesis when Wnt signaling triggers progenitors within the epithelial sheet to organize spatially into morphologically similar placodes. Whereas most mammals restrict the specification of epidermal appendages regionally, HFs and sweat glands (SwGs) coexist throughout much of the skin of primates. The acquisition of SwGs and their importance in thermoregulation are underscored by humans who suffer from a life-threatening condition when SwGs are eliminated, either from loss in severe burns or from the genetic disorder hypohidrotic ectodermal dysplasia (HED).Patients with HED display mutations in genes encoding proteins such as ectodermal dysplasia antigen (EDA), the EDA receptor (EDAR), and WNT10a, a ligand for Wnt signaling. These findings have illuminated a critical role for these pathways in controlling the development of a number of epidermal appendages, including SwGs and coarse hairs (1, † Corresponding author. fuchslb@rockefeller.edu. * Present address: Calico Life Sciences, South San Francisco, CA 94080, USA.RNAseq data are deposited in the Gene Expression Omnibus under accession number GSE85249 (www.ncbi.nlm.nih.gov/geo).The authors declare no competing financial interests. SUPPLEMENTARY MATERIALS Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 2). Conversely, an EDAR gain-of-function variant has been expanding among the Southeast Asian population, where excessive SwGs are desirable because of the hot and humid climate of that region (3). In this regard, both Wnt and EDA/EDAR pathways appear to function in promoting placode formation, increasing the density of SwGs and several other appendage types (4).Classical tissue recombination experiments have revealed that mesenchyme plays a critical role in dictating the divergent downstream events that determine appendage selection (5, 6). For example, salivary mesenchyme combined with mammary epithelium generates an epithelial morphology resembling salivary glands (7), and...

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Involvement of Wnt, Eda and Shh at defined stages of sweat gland development

Cited by 60 publications

References 50 publications

Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development

Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development

A genetic basis of variation in eccrine sweat gland and hair follicle density

839 Spatiotemporal antagonism in mesenchymal-epithelial Signaling in sweat versus hair fate decision

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