p63 in skin development and ectodermal dysplasias

Abstract

The transcription factor p63 is critically important for skin development and maintenance. Processes that require p63 include epidermal lineage commitment, epidermal differentiation, cell adhesion, and basement membrane formation. Not surprisingly, alterations in the p63 pathway underlie a subset of ectodermal dysplasias, developmental syndromes in which the skin and skin appendages do not develop normally. This review summarizes the current understanding of the role of p63 in normal development and ectodermal dysplasias.

Figure 1. p63 in developmental disorders

Mutations in p63 or p63 target genes cause developmental disorders. Dominant mutations in p63 underlie AEC, EEC, and SHFM4, whereas dominant mutations in the p63 target genes P-cadherin, Dlx3, and Dlx5/6 underlie EEM, TDO, and SHFM1, respectively. Common features of EEC, EEM, and SHFM include severe limb abnormalities, including syndactyly and ectrodactyly (right image; image depicts an EEC patient). A characteristic feature of AEC patients is the presence of severe erosions, often located to the scalp (left image). Other ectodermal dysplasias caused by mutations in p63 include limb-mammary syndrome (LMS) and acro-dermato-ungual-lacrimal-tooth syndrome (ADULT). Images of AEC and EEC patients were provided by the National Foundation for Ectodermal Dysplasias (NFED).

Figure 2. Mutations in different domains of p63 cause different ectodermal dysplasias

The p63 gene is expressed as multiple isoforms. Isoforms depicted here are the full-length isoform, TAp63α, and the predominantly expressed p63 isoform in late embryonic and postnatal epidermis, ΔNp63α. Mutations in the DNA binding domain, common to all p63 isoforms, can cause EEC or SHFM4. Mutations in the ΔN N-terminus or the SAM domain (only present in the α C-terminus) underlie AEC. For an overview of p63 mutations found in ectodermal dysplasia patients, please see these references (Rinne et al., 2007;Rinne et al., 2008). TA: transactivation domain, oligo: oligomerization domain, SAM: sterile alpha motif.

Figure 3. Role of p63 in the epidermis

The epidermis is a stratified epithelium, which consists of several layers of keratinocytes (indicated on left). When interfollicular stem cells, which reside in the basal layer, divide, they give rise to transit amplifying cells which constitute most of the basal layer. When transit amplifying cells initiate terminal differentiation, they withdraw from the cell cycle and move suprabasally, forming the spinous layer. Further differentiation results in the formation of the granular and cornified cell layers. p63 is involved in various processes required for epidermal development, differentiation, and homeostasis (indicated on right). Genes involved in these processes are indicated in the text.