Onecut transcription factors in development and disease

Abstract

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.

Keywords: liver; nervous system; onecut; pancreas; transcription factor.

Figure 1. Implications of Oc1 loss in disease

The pancreas and liver, both endodermally-derived organs, are impacted by loss of Oc1 during development and disease. Top: Oc1 heterozygosity causes defects in glycogen breakdown, resulting in increased glycogen stores in the liver, as shown by Periodic Acid Schiff staining in 3-week old mouse livers (pinkish purple). Bottom: Oc1 is expressed in the nuclei of normal, healthy ducts and acini of human pancreas. Its expression is lost entirely from lesions of pancreatic ductal adenocarcinoma (PDAC).

Figure 2. Network of Oc factor targets and associated processes

Oc factors regulate a common network of transcription factors in different tissues during development to promote differentiation of multiple different mature cell types. This regulation carries over to function of mature cells in the liver through regulation of glucose-processing enzymes.

Figure 3. Common targets and co-factors of Oc factors

The Oc factors operate within common gene expression networks in multiple different tissue types. Shown here, the ectodermally-derived tissues (retina and neurons; light gray) and endodermally-derived tissues (hepatobiliary and pancreas; darker gray) share many of the same downstream targets that promote development of their respective cell types.