Study Finds Two Genes that Play Key Role in Epithelial Development

A study in eLife has found two regulator genes that may be key suspects in cleft lip, skin barrier defects, and a host of other developmental problems in mice.

Previous research showed that the two genes—Esrp1 and Esrp2—are active specifically in epithelial cells, which form the skin, the inner layers of the gut and lung, and other tissues in the body. The two genes have recently come under investigation due to their potential prominence in the development of certain types of cancer.

The study results suggested that abnormalities in these molecular pathways could underlie many birth defects presently misunderstood. The two closely related regulatory genes are active in the normal development of mammals and govern how RNAs produced from the genes are joined to make final versions of the encoded protein, a process called alternative splicing.

“Esrp1 and Esrp2 are two proteins that regulate alternative splicing in epithelial cells,” the study authors note. “These specialized cells form sheets that line most organs in the body and are found in the epidermis, the outermost layer of the skin. Although Esrp1 and Esrp2 have previously been studied in the laboratory using cultured cell lines, their roles have not been investigated in living animals.”

The researchers engineered mice without Esrp1, Esrp2, or both. Mice lacking Esrp1 alone were born alive, but with cleft palate and cleft lip deformities that prevented feeding.

All died within hours.

Interestingly, mice lacking only Esrp2 appeared normal, as long as Esrp1 was present, suggesting that perhaps Esrp2 has evolved as a sort of “backup” in case something happens to development of Esrp1. Mice engineered with neither gene had significant defects, including craniofacial defects and the absence of key organs such as the lungs and salivary glands — two organs made up largely of epithelial cells.

The researchers noted that further determination of epithelial specific splice variants could provide molecular insights into novel genes underlying the pathogenesis of cleft lip and palate (CL/P).

“The knockout of Esrp proteins in mice provides the first evidence for a requirement for these cell-type-specific splicing factors in embryonic development and epithelial cell functions,” the study authors conclude. “The identification of the Esrp regulated splicing program provides numerous examples of genes that merit further investigation into their developmental functions and contribution to human diseases such as CL/P and diseases associated with epithelial barrier defects. A challenge for future studies will be to functionally dissect the molecular mechanisms by which some of these isoform-specific activities are involved in maintenance not only of epithelial barriers, but also in mediating epithelial-mesenchymal crosstalk during development and maintaining other properties of epithelial cells.”