ZEB2

ZEB2, also known as Zfhx1b or SIP1, is a human transcription factor that contains multiple C2H2 zinc-finger domains and primarily acts as a transcriptional repressor. It binds E-box DNA sequences and interacts with SMAD proteins to regulate gene expression in response to TGF-β signaling, influencing epithelial-mesenchymal transition and related developmental processes.

The ZEB2 gene is located on chromosome 2q22-q23. Haploinsufficiency of ZEB2 causes Mowat-Wolff syndrome, a neurodevelopmental disorder characterized by distinctive facial features, Hirschsprung disease, agenesis of the corpus callosum, and varying degrees of intellectual disability and motor impairment.

During development, ZEB2 plays essential roles in neural crest cell formation and migration, neural tube and enteric nervous system development, and other processes requiring epithelial-menchymal transitions. It commonly promotes the mesenchymal state by repressing epithelial markers such as E-cadherin (CDH1) and regulating the expression of mesenchymal and other differentiation-associated genes.

In signaling networks, ZEB2 functions at the intersection of TGF-β/BMP pathways, modulating transcription in response to Smad activation. Its activity is tightly regulated by microRNAs, including the miR-200 family, which target ZEB2 to influence EMT dynamics.

In cancer biology, ZEB2 has been linked to promoting EMT and metastasis in several cancers, contributing to invasiveness and resistance to therapy in a context-dependent manner. Animal models, including mice with Zeb2 mutations, show defects consistent with neural crest and CNS abnormalities, underscoring ZEB2’s critical role in development and disease.