Spatiotemporal Expression of p63 in Mouse Epidermal Commitment

Zhao, Qian; Liu, Shuang; Zhang, Huishan; Li, Na; Wang, Xinyue; Cao, Yuqi; Ning, Lina; Duan, Enkui; Xia, Guoliang

doi:10.3390/ijms161226185

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…These findings support a model in which p63 is essential for epidermal commitment, acting as a gatekeeper of the epithelial lineage (14). Consistent with this model, expression of p63 in mouse embryos is firstly induced in the surface ectoderm where Krt8 and Krt18 are expressed, and continuously increased during epidermal commitment (16). An alternative model is that p63 is not required for commitment towards the epidermal fate, as it was reported that a small number of Krt5 and Krt14 expressing cells was observed and that the morphology of cells and tissues was relatively normal in p63 knockout mice (5).…”

Section: Introductionsupporting

confidence: 85%

Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome

Soares¹,

Xu²,

et al. 2018

Preprint

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Mutations in transcription factor p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. The underlying cellular and molecular mechanism ishowever not yet understood. We established an epidermal commitment model using human induced pluripotent stem cells (iPSCs) and characterized differentiation defects of iPSCs derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations.Transcriptome analyses revealed distinct step-wise cell fate transitions during epidermal commitment; from multipotent simple epithelium to basal stratified epithelia, and ultimately to the mature epidermal fate. Differentiation defects of EEC iPSCs caused by mutant p63 occurred during the specification switch from the simple epithelium to the basal stratified epithelial fate. Single-cell transcriptome and pseudotime analyses identified signatures of embryonic epithelial-mesenchymal transition (EMT) associated with the deviated commitment route of EEC iPSCs. Repressing mesodermal activation reversed the EMT and enhanced epidermal commitment. Our findings demonstrate that p63 is required for specification of stratified epithelia, probably by repressing embryonic EMT during epidermal commitment. This study provides insights into disease mechanisms underlying stratified epithelial defects caused by p63 mutations and suggests potential therapeutic strategies for the disease. Significance statementMutations in p63 cause several developmental disorders with defects of epithelial related organs and tissues including the epidermis. Our study is to dissect the unknown cellular and molecular pathomechanism. We utilized human induced pluripotent stem cells (iPSCs) derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations and studied transcriptome changes during differentiation of these cells to epidermal cells. Our analyses showed that the specification of the proper epithelial cell fate was affected by p63 EEC mutations, with an abnormal embryonic epithelial-mesenchymal transition (EMT). Repressing mesodermal activation reversed the EMT and enhanced epidermal commitment. This study provides insights into disease mechanisms associated with p63 mutations and suggests potential therapeutic strategies. embryonic development (reproduction) as well as cell proliferation. Genes in cluster 4, e.g. IGFBP3 and GATA3, were induced during early epidermal differentiation and stayed at a high level until differentiation day 30. Many of these genes seemed to play roles in cell migration and adhesion, embryonic morphogenesis and development of different organs such as epithelium, vasculature and skeletal system development. Importantly, cluster 5 included genes such as KRT5, KRT17 and TP63 that are involved in epithelial and epidermal development, desmosome assembly and extracellular matrix organization. These genes were lowly expressed in PSCs and during early differentiation, and 7 significant...

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Section: Introductionsupporting

confidence: 85%

Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome

Soares¹,

Xu²,

et al. 2018

Preprint

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“…Recently, spatio-temporal expression of p63 during normal mouse embryonic development was analyzed [ 26 ]. p63 expression was detected in ectodermal cells near the newly formed somites and the posterior part of the E8.5 embryo, preceding epidermal commitment.…”

Section: P63 Is Essential For Proper Epidermal Commitmentmentioning

confidence: 99%

Master regulatory role of p63 in epidermal development and disease

Soares

Zhou

2017

Cell. Mol. Life Sci.

147

145

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The transcription factor p63 is a master regulator of epidermal development. Mutations in p63 give rise to human developmental diseases that often manifest epidermal defects. In this review, we summarize major p63 isoforms identified so far and p63 mutation-associated human diseases that show epidermal defects. We discuss key roles of p63 in epidermal keratinocyte proliferation and differentiation, emphasizing its master regulatory control of the gene expression pattern and epigenetic landscape that define epidermal fate. We subsequently review the essential function of p63 during epidermal commitment and transdifferentiation towards epithelial lineages, highlighting the notion that p63 is the guardian of the epithelial lineage. Finally, we discuss current therapeutic development strategies for p63 mutation-associated diseases. Our review proposes future directions for dissecting p63-controlled mechanisms in normal and diseased epidermal development and for developing therapeutic options.

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“…As we have described in chapter 2, the simple epithelia-specific keratin pair, K8/K18, are expressed in keratinocyte progenitors, early on during embryonic skin development, and upon vertical epidermal stratification K8/K18 expression is then substituted by K5/K14, and becomes eventually lost in fully mature skin epidermis [9,10,74]. Overexpressing human K8 in mouse epidermis (TGHK8 mice) lead to severe epidermal phenotypes including epidermal hyperplasia associated with orthokeratotic hyperkeratosis, dysplastic hair follicles and altered expression terminal differentiation markers [75].…”

Section: Sccs and K8/k18mentioning

confidence: 97%

Keratins in Skin Epidermal Development and Diseases

Zhang¹

2018

Keratin

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Epidermal keratinocyte (KC), the major cell type in the skin epidermis, plays critical roles in forming a permeability barrier to separate internal organs from external stimuli. Keratins, constituting about 30-80% of the total protein in KCs, form the major intermediate filament cytoskeleton of KC. Keratins consist of 54 unique genes in humans and they are expressed in cell-, differentiation-and development-dependent manner. While keratin pairs K5-K14 and K1-K10 are normally associated with KCs at different cell differentiation stages, other keratin pairs such as K6-K16/K17 and K8-K18 and are usually not expressed in normal skin interfollicular epidermis, but are elevated during wounding, inflammatory skin diseases such as psoriasis or malignant conversion of KC. The expression and function of keratins are tightly regulated at both transcriptional and post-transcriptional levels. Inherited or spontaneous mutations in keratins or abnormal keratin regulations or modifications can cause KC and cutaneous tissue fragility, skin hypertrophic and inflammatory conditions or malignant transformation of KC, therefore accounting for a large number of disorders in human skin. Here we review the recent literature on how keratins are normally expressed during skin development and how mutations or misregulations of these keratins are involved in the pathogenesis of skin diseases.

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Spatiotemporal Expression of p63 in Mouse Epidermal Commitment

Cited by 7 publications

References 41 publications

Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome

Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome

Master regulatory role of p63 in epidermal development and disease

Keratins in Skin Epidermal Development and Diseases

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