Developmental processes are remarkably well conserved among species, and among the most highly conserved developmental regulators are transcription factor families. The Onecut transcription factor family consists of three members known for their single “cut” DNA-binding domain and an aberrant homeodomain. The three members of the Onecut family are highly conserved from Drosophila to humans and have significant roles in regulating the development of diverse tissues derived from the ectoderm or endoderm, where they activate a number of gene families. Of note, the genetic interaction between Onecut family members and Neurogenin genes appears to be essential in multiple tissues for proper specification and development of unique cell types. This review highlights the importance of the Onecut factors in cell fate specification and organogenesis, highlighting their role in vertebrates, and discusses their role in the maintenance of cell fate and prevention of disease. We cover the essential spatial and temporal control of Onecut factor expression and how this tight regulation is required for proper specification and subsequent terminal differentiation of multiple tissue types including those within the retina, central nervous system, liver and pancreas. Beyond development, Onecut factors perform necessary functions in mature cell types; their misregulation can contribute to diseases such as pancreatic cancer. Given the importance of this family of transcription factors in development and disease, their consideration in essential transcription factor networks is underappreciated.
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