P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle

Abstract

*P-cadherin is a member of the classical cadherin family that forms the transmembrane core of adherens junctions. Recently, mutations in the P-cadherin gene (CDH3) have been shown to cause two inherited diseases in humans: hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). The common features of both diseases are sparse hair and macular dystrophy of the retina, while only EEM syndrome shows the additional finding of split hand/foot malformation (SHFM). We identified five consanguineous Pakistani families with either HJMD or EEM syndrome, and detected pathogenic mutations in the CDH3 gene of all five families. In order to define the role of P-cadherin in hair follicle and limb development, we performed expression studies on P-cadherin in the mouse embryo, and demonstrated the predominant expression of P-cadherin not only in the hair follicle placode, but also at the apical ectodermal ridge (AER) of the limb bud. Based on the evidence that mutations in the p63 gene also result in hypotrichosis and SHFM, and that the expression patterns of p63 and P-cadherin overlap in the hair follicle placode and AER, we postulated that CDH3 could be a direct transcriptional target gene of p63. We performed promoter assays and ChIP, which revealed that p63 directly interacts with two distinct regions of the CDH3 promoter. We conclude that P-cadherin is a newly defined transcriptional target gene of p63, with a crucial role in hair follicle morphogenesis as well as the AER during limb bud outgrowth in humans, whereas it is not required for either in mice.

P-cadherin role in normal breast development and cancer

“…Importantly, the authors showed that p63 expression caused downregulation of cell adhesion-associated genes and detachment between mammary epithelial cells (Carroll et al, 2006). This involvement of p63 in cell adhesion mechanisms was finally linked with CDH3 gene, when Shimomura and colleagues demonstrated that P-cadherin is a direct p63 transcriptional target and that this interplay has a crucial role in human limb bud and hair follicle development (Shimomura et al, 2008) (Fig. 3).…”

“…However, it is known that during bud patterning, a special arrangement occurs, where cells change their interaction with their neighbours and break their attachments to the extracellular matrix (ECM). Cells achieve this by activating specific transcriptional programs (Shimomura et al, 2008).…”

Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation

“…30,31 Moreover, many genes, including SHFM diseasecausing genes such as TP63 and WNT10b, are expressed in this region. 32,33 DLX5 and DLX6 are very similar in that, both are candidate genes for SHFM1, tandemly arranged on locus 7q21 tail to tail and are expressed in the median AER of embryonic limb buds. Simultaneous knockout of DLX5 and DLX6 in the mouse results in the SHFM phenotype.…”

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1 MET

“…Four genes that were previously shown to be elevated in WT mice but not in p63-null mice at E14.5 (GJA1, GJ6B, KRT14, KRTDAP) (19) were rescued by APR-246. Moreover, the level of expression of three p63-target genes (DLX5, DLX6, and CDH3/P-Cadherin) that are known to be associated with EEC syndrome (20,21) was significantly enhanced by APR-246. Interestingly, we found that APR-246 acted differently on the R204W and R304W mutants.…”