Functional analysis of ZFHX1 family transcription factors in embryonic development

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ZFHX1 family of transcription factors, containing highly conserved two-partite zinc finger clusters and a homeodomain, comprises δEF1 (δ-crystallin enhancer factor 1) and SIP1 (Smad-interacting protein 1) in higher vertebrates. In mouse embryo, expression of these protein genes overlap extensively in some tissues (e.g., neural plate and cranial ganglia) and often also take place in adjacent domains of the same tissue (e.g., cranial mesenchyme and neural tube). To investigate the functional relationships between these two factors, we generated compound knockout mouse embryos and investigated the resulting phenotype. SIP1-/- homozygous embryos develop morphological abnormality after E8, defect in anterior neural plate closure, arrest of migration of cranial neural crest, and defective somitogenesis ; by contrast, δEF1-/- homozygous embryos display mild defects only after mid-gestation period. δEF1-/- ; SIP1-/- double homozygous einbryos show severer phenotype than SIP1-/- homozygous embryo in the anterior neural plate, namely thin neural plate without a clear morphological boundary to the non-neural ectoderm. The severity of this phenotype is highly correlated with decrease of Sox2 expression level. As SIP1-/- homozygous embryos die after E9, effect of compounded deficiency of ZFHX1 proteins was examined under the condition of δEF1-/- ; SIP1+/-. Under this condition, various morphological defects either not observed in δEF1-/- homozygous embryos (e.g., disorganized development of brain ventricles, and open neural tube in the tail) or in strengthened form of milder defects in δEF1-/- homozygous embryos (e.g., craniofacial abnormality). These phenotypes of the compound mutants indicate that δEF1 and SIP1 have primarily redundant functions where their expression overlaps.