Programmed cell death not as vital as originally thought

Researchers at the Walter and Eliza Hall Institute (WEHI) have made a discovery that could rewrite our understanding of the role programmed cell death (apoptosis) plays in embryonic development and congenital birth defects, revealing that while the process is essential for healthy development overall, many organs and tissues do not require apoptosis in order to develop normally.

Apoptosis is a normal process that rids the body of sick, damaged or unwanted cells in a controlled way, limiting side effects and damage to the body. It was first described as having a role in embryonic development in the 1940s, and numerous studies over the past 70 years have implicated apoptosis as playing a crucial role in most stages and tissues during development.

“For some time, it has been a widely held belief that programmed cell death is necessary for the shaping of certain tissues and structures during development,” said co-lead researcher Associate Professor Anne Voss.

But the latest study, published in the journal Cell, makes it clear that apoptosis was not as critical during development as previously thought. “Rather,” said co-lead researcher Dr Francine Ke, “apoptosis was essential at specific places and times during development, but unnecessary in others.

“We identified the tissues and organs that critically require apoptosis to develop normally, and made the surprise discovery that many do not require it at all.”

Associate Professor Voss said she was surprised by the number of tissues that did not require apoptosis at all for normal development, including some in which it was previously considered “absolutely essential”.

“For example, apoptosis was thought to play a particularly important role in ‘hollowing out’ of ducts in internal organs during development,” she said.

“However, we have shown that — in the absence of apoptosis — most tissues and organs develop normally. I think it may surprise researchers to learn just how precise and limited the effects of apoptosis are in embryonic development.”

The study also suggested that abnormalities in cell death processes are likely to contribute to some common birth defects in humans, such as spina bifida, heart vessel defects and cleft palate. As explained by Dr Ke, “Our research showed that when cell death is not functioning properly, it commonly leads to defects in neural tube development.”

To determine the role of apoptosis in development, the team eliminated pro-death proteins BAK and BAX, and a similar protein BOK, whose function was unclear until now. Co-lead researcher Dr Angus Cowan said the study confirmed that BOK acted as a pro-death protein.

“In this paper we have solved the structure of BOK using the Australian Synchrotron, and once and for all confirmed that BOK is a pro-death protein that plays an important role in apoptosis,” he said.

Image caption: Dr Francine Ke, Dr Angus Cowan and Associate Professor Anne Voss. Image credit: Walter and Eliza Hall Institute.