UCLA stem cell scientists take hedgehog signaling up a Notch

Human development begins with a few cells that will ultimately divide and give rise to trillions of cells in the adult body. The development process requires precise communication between dividing cells as they coordinate their activities and actions. This communication, called cell signaling, is critical in the development of a healthy human – one small change in the signaling pathways between cells during development can cause hundreds of different types of complications, from birth defects such as missing fingers or toes to diseases that manifest throughout life, such as cancer. A better understanding of cell signaling processes could help researchers develop new or improved treatments for many human diseases and conditions.

Published online today in the journal Developmental Cell, research from scientists led by Bennett Novitch, Ph.D., at the Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA significantly furthers the understanding of two major signaling pathways linked to a host of diseases.

About seven leading cell signaling pathways are crucial in fetal development. These developmental pathways continue to be important in maintaining healthy bodily systems throughout life. However, questions regarding how different signaling pathways interconnect and influence cell development remain largely unanswered. Novitch’s research used the developing spinal cord and neural stem cells as a model to shed light on two of the most fundamental pathways in cell development – ‘Notch’ and ‘Sonic Hedgehog’ – in order to understand how the two pathways impact one another. The research shows a significant connection between these two pathways as they work together to influence fetal development.

“Our study is the first to suggest a mechanistic connection between Notch and Sonic Hedgehog signaling pathways; we found that the activity of the Notch pathway alters the activity of the Sonic Hedgehog pathway,” said Novitch, an associate professor of neurobiology at UCLA and senior author on the study. “It’s an unexpected convergence of two of the most important developmental signaling pathways.”

Several factors influence the process of cell signaling, including the type of signal, the amount of the signal the cell receives, the time cells are exposed to the signal, the state of the cells during signaling and how the signal is processed by the cell. Novitch, the study’s lead author Jennifer Kong and their team sought to understand how all of these mechanisms influence neural stem cells exposed to Notch and Sonic Hedgehog signaling.

Notch signaling is important because it has the ability to expand progenitor cells when stimulated and reduce progenitor cells when inactivated. While all embryonic stem cells start in a pluripotent state, meaning they can turn into any cell in the body, as development progresses, the cells are assigned to different parts of the body. These tissue-specific cells are called progenitor cells. Progenitor cells can replicate a limited number of times to produce cells within their designated tissue. For example, a pluripotent stem cell can become a neural cell or a blood cell but a neural progenitor cell can only turn into different cells within the nervous system and cannot become a blood cell. Where progenitor cells exist in the body, Notch signaling also exists in order to maintain the progenitor state. If Notch signaling doesn’t occur, cells exit the progenitor state and are no longer capable of replicating.

Sonic Hedgehog signaling, governed by the Sonic Hedgehog gene, is crucial for normal embryonic development of the brain, spinal cord, eyes, limbs and many other parts of the body. The unique name comes from the Sega Genesis video game ‘Sonic the Hedgehog’ popular in the 1990s. Despite its whimsical name, Sonic Hedgehog is one of the most important signaling pathways in development, as the level of Sonic Hedgehog protein must be perfectly balanced. Any increase or decrease can cause major birth defects, from missing fingers or toes or an unusual distance between the eyes to an abnormally formed brain. Overactive Sonic Hedgehog cell signaling can also contribute to the development of a number of brain tumors and skin cancer. Importantly, Sonic Hedgehog cell signaling primarily occurs while cells are in a progenitor state, resulting in the close interrelationship with Notch signaling.

In the study, Novitch and his team found that increasing or decreasing Notch signaling alters how neural stem cells respond to Sonic Hedgehog, showing that Notch signaling directly influences how much of the Sonic Hedgehog protein cells receive during development. When Notch signaling is activated, cells act as if they have encountered a higher dose of Sonic Hedgehog signaling. When Notch signaling is inactive, cells act as if they’ve received a lower dose. Moreover, they found that Notch signaling controls the movement of certain parts of Sonic Hedgehog signaling to special structures on the cells called primary cilia. Primary cilia are small protrusions that resemble eyelashes; they are found on nearly every stem or progenitor cell in the body. Like a receptionist, primary cilia process messages sent between cells and translate the information to regulate the actions of genes within the cell. Disruptions in the movement of proteins to primary cilia results in many genetic diseases collectively referred to as ciliopathies, which impact the eyes, kidneys, brain, liver, skeleton and other organ systems. The study showed that altering Notch cell signaling can affect ciliary functions, implicating it as a potential contributor to ciliopathies.

“By understanding more about how the Sonic Hedgehog and Notch signaling pathways function together, we hope to be able to one day devise more effective therapies to prevent birth defects and treat conditions such as ciliopathies and certain types of cancers,” said Novitch.

The next step in Novitch’s research is to identify how Notch signaling modifies the movement of proteins to and from primary cilia. He also plans to study if the relationship between Notch and Sonic Hedgehog signaling applies to other signaling pathways that similarly rely on the movement of proteins to primary cilia.

This work was supported by grants from the March of Dimes Foundation, the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, the Medical Research Council (UK) and the Wellcome Trust as well as support from the Rose Hills Foundation and the UCLA Broad Stem Cell Research Center.