Study Identifies Important Regulator of Hedgehog Pathway

A new study co-led by a Cedars-Sinai investigator has identified a gene that plays an important role in a biological pathway involved in embryo development. The gene's impact at the cellular level could explain why some babies are born with physical abnormalities and why some adults develop diseases such as cancer.

Human embryonic development involves many complex cellular processes that proceed via signaling pathways that activate molecules in a cell to guide its functions. For this study, investigators sought to better understand the so-called Hedgehog signaling pathway, which regulates growth of the human embryo and is also active in adulthood. They discovered that the gene Cnpy4 can affect the ability of a cell to carry out this pathway.

“There are a handful of signaling pathways that are critical regulators of all biological processes that occur during development and are also involved in disease, so we want to understand how these pathways function,” says Ophir Klein, MD, PhD, co-senior author of the study and executive director of Cedars-Sinai Guerin Children's. “What we've identified here is a gene that is a very important modulator of the critical Hedgehog pathway.”

The investigators observed that laboratory mouse embryos with a mutation in the Cnpy4 gene were born with polydactyly, a birth defect involving extra fingers or toes. Some of the mice also had abnormalities in their spines and ribs. Prior studies have shown that alterations to the Hedgehog pathway can cause these congenital malformations.  

The study also found that the Cnpy4 gene affects levels of lipids found on the cellular membrane. These changes in lipid levels affect an important protein called Smoothened that is a vital component of the Hedgehog pathway. Mice that lacked Cnpy4 had elevated levels of accessible cholesterol on their cellular membranes, which caused Smoothened to signal more strongly. This led to hyperactivity of the pathway and the uncontrolled generation of new cells.

“This pathway is one of a handful that are central to human development,” says Klein, who holds the David and Meredith Kaplan Distinguished Chair in Children's Health at Cedars-Sinai. “And because the same pathways are affected in various disorders, we think they could be a target for therapies for cancers that we know are related to Hedgehog signaling.”

The findings were published in Nature Communications.