The phenotypic changes seen in EMT result from repression of epithelial specification genes by a set of related transcriptional repressors, including Snail (Snai) and
zinc finger
E-box
binding homeodomain (Zeb) family members (Zeb1, also known as TCF8, δ-EF1, ZFHX1A, and Zfhep and Zeb2, also know as Smad-interacting protein 1; reviewed in
6 ). These EMT transcription factors bind overlapping sets of E-box promoter elements to repress epithelial specification genes such as E-cadherin. They become overexpressed in cancer and in fibrotic responses,
7–12 and overexpression of any one of them appears sufficient to initiate EMT.
5 In Zeb1 mutants, mesenchymal progenitors in the craniofacial region and skeleton and neural progenitors in the CNS ectopically express epithelial markers including E-cadherin and cytokeratins, and they show proliferative defects.
13 Accordingly, late-stage mutant embryos have severe craniofacial defects, skeletal curvatures, and shortened limbs and digits, and a subset of the embryos has a severe neural phenotype, with failure of neural tube closure at both cranial and caudal ends leading to exencephaly.
14 Although
Zeb1 heterozygous mice are viable, they show defective smooth muscle cell (mesenchymal) differentiation in response to vascular injury, leading to increased neointima formation.
15 No defect in smooth muscle formation was evident in heterozygous mice before vascular injury, implying that this decrease in
Zeb1 dosage is crucial only in response to injury. However, it has been demonstrated recently that heterozygous mutation of
Zeb1 is responsible for posterior polymorphous corneal dystrophy (in both humans and mutant mice), which is characterized by a pathologic epithelial transition of the corneal endothelium, leading to corneal dysfunction.
16–18 Thus, in some tissues, decreasing the level of Zeb1 by heterozygous mutation appears sufficient to drive an epithelial-like transition in the absence of injury.