Transcriptional control of epidermal specification and differentiation

doi:10.1016/j.gde.2004.07.002

Current Opinion in Genetics & Development

Volume 14, Issue 5, October 2004, Pages 485-491

https://doi.org/10.1016/j.gde.2004.07.002 Get rights and content

Recent experiments reveal the role of transcription factors in integrating upstream signals to execute specification and differentiation of epidermal cells. Based on the skin phenotype observed with misregulation of transcription factors such as p63, c-Myc, RelA, pRb, Klf4 and others, their function in controlling proliferation and differentiation is dissected. Understanding the pathways regulated by these factors and their coordinate interactions remains a challenge for the future.

Introduction

Recent experiments have provided extensive new insight into the regulation of proliferation, differentiation, cell-fate determination, and pattern formation of mammalian epidermis. The epidermis is established in utero and replenished from a pool of adult stem cells (SCs), which give rise to interfollicular epidermis (IFE), hair follicles, and sebaceous and sweat glands. Perturbations to the normal balance of differentiation and proliferation can result in skin disorders including cancer. Therefore, understanding the molecular and genetic control of this process is of immense medical and pharmaceutical relevance.

Regulation of gene expression is at the heart of all development and differentiation processes. Transcription factors (TFs) integrate and interpret signals from upstream developmental/growth factor signaling pathways in a coordinate and complex fashion to execute downstream differentiation/morphogenetic events. Here, we review recent progress made on understanding the role of TFs in regulating epidermal SC maintenance and the orderly progression of interfollicular terminal differentiation.

Section snippets

Stem cell maintenance and proliferation

An emerging topic of intense focus has been defining and characterizing the epidermal SCs (for reviews, see 1., 2.). Recent transcriptional profiling studies provide fodder for years of future experimentation and insights into how gene expression might be regulated during SC renewal and differentiation 3.••, 4.••. Key regulators of SC maintenance and epidermal proliferation include p63, c-Myc, Gli and Id TFs (Figure 1).

The essential role of p63, a homolog of the p53 tumor suppressor, in skin

Initiation and progression of terminal differentiation

Terminal differentiation of the IFE can be divided arbitrarily into three steps: growth arrest, initiation of differentiation, and terminal differentiation. Not all studies offer this resolution because strong homeotic control of skin often leads to concomitant defects in growth and differentiation. Where a step-specific function is suggested, clues have often come from other systems or analysis of putative downstream targets. Here we discuss TFs that are involved in driving the differentiation

Conclusions and perspectives

A comprehensive picture of the genetic pathways governing epidermal differentiation remains in infant form. Two major advantages of this system are the ability to move between in vitro and in vivo and to modulate gene expression with promoters specific to the different layers of the epidermis. Looking into the future, sophisticated genetic approaches such as crossing mutants of different components of a particular pathway, analysis of tissue-specific, isoform-specific, and double even triple

Update

Gerondakis’s group [56^•] circumvents the embryonic lethality of RelA and c-rel deficient mice by placing them on a tumor necrosis factor alpha deficient background. The compound c-rel^−/− RelA^−/− epidermis is thinner with more proliferative basal cells, which fail to form colonies in vitro. The c-rel^−/− RelA^−/− neonates do not survive, and the grafted skin is relatively normal although immune responsive hyperproliferation is observed.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We thank Satrajit Sinha for his helpful suggestions and critical review of this manuscript and Mike Cichanowski for his assistance with the artwork. X Dai is supported by an NIH Research Grant R01 AR47320 and a US Army Grant W81XWH-04-1-0516.

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Reducing the expression of p53 inhibits the Fas pathway and thus the ectopic apoptotic pathway, and local treatment with Pifithrin-α which is a p53 inhibitor has been shown to have a beneficial stimulatory effect on hair restoration and growth. p63 has been shown to play a unique role in stem cell maintenance and proliferation, including epidermal stratification and epithelial stem cell growth (Pellegrini et al., 2001; Dai et al., 2004; Kai-Hong et al., 2007). p63 downregulation inhibits epidermal stratification and differentiation (Truong et al., 2006).
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View full text

Transcriptional control of epidermal specification and differentiation

Introduction

Section snippets

Stem cell maintenance and proliferation

Initiation and progression of terminal differentiation

Conclusions and perspectives

Update

References and recommended reading

Acknowledgements

Cell

J Invest Dermatol

Curr Biol

Development

Nat Genet

Development

J Invest Dermatol

Development

Nature

Proc Natl Acad Sci USA

Profiling epithelial stem cells

Nat Biotechnol

Defining the epithelial stem cell niche in skin

Science

Capturing and profiling adult hair follicle stem cells

Nat Biotechnol

p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development

Nature

p63 is a p53 homologue required for limb and epidermal morphogenesis

Nature

p63 is the molecular switch for initiation of an epithelial stratification program

Genes Dev

On the shoulders of giants: p63, p73 and the rise of p53

Trends Genet

Down-regulation of p63 is required for epidermal UV-B-induced apoptosis

Cancer Res

deltaNp63alpha functions as both a positive and a negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes

Oncogene

c-Myc promotes differentiation of human epidermal stem cells

Genes Dev

Deregulated expression of c-Myc depletes epidermal stem cells

Nat Genet

Targeted expression of c-Myc in the epidermis alters normal proliferation, differentiation and UV-B induced apoptosis

Oncogene

Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion

Mol Cell

Sonic hedgehog opposes epithelial cell cycle arrest

J Cell Biol

Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development

Genes Dev

Id proteins are dynamically expressed in normal epidermis and dysregulated in squamous cell carcinoma

Cancer Res

Immortalization of primary human keratinocytes by the helix-loop-helix protein, Id-1

Proc Natl Acad Sci USA

Id-1 delays senescence but does not immortalize keratinocytes

J Biol Chem