Worms win, coming and going

NORTHWESTERN (US) — A tiny flatworm that is able to regenerate itself no matter what tragedy befalls it may offer clues to tissue regeneration and repair in humans.

An ancient and seldom studied gene is crucial to the planarian flatworm’s ability to regenerate its entire body—or single parts including muscle, neurons, epidermis, eyes, and brain—from a single wedge of tissue. When cut in half, it becomes two worms.

Protein from the notum gene determines whether a head or tail will regrow at the amputation site.

“These worms are superstars in regeneration, and we want to learn how they restore missing body parts,” says Christian Petersen, assistant professor of molecular biosciences at Northwestern University. “We anticipate that understanding the details of how regeneration occurs in nature will ultimately have a broad impact on the repair of human tissue.”

The study is published in the journal Science.

Planarians ability to regenerate tissue depends on a pool of adult stem cells. Researchers hope that studying them will clarify the molecular processes that naturally allow stem cell-mediated tissue repair in higher animals.

Petersen and Peter Reddien, associate professor of biology at Massachusetts Institute of Technology, show that the gene notum is critical for head regeneration in planarians. Inactivation of notum caused animals to regenerate a tail instead of a head, creating two-tailed animals.

“Injuries can alter tissues in many different ways, so regenerating animals must have robust systems that specify restoration of appropriate structures,” Petersen says. “Our results suggest that the animals ‘decide’ what needs to be regenerated, in part, by using cues that indicate axis direction with respect to the wound.”

Planarians are 2 to 20 millimeters in size, have a complex anatomy with around a million cells, and live in freshwater ponds and streams around the world. The worm’s genome has been sequenced, and its basic biology is well-characterized, making planarians popular with scientists.

Notum controls a widely used biochemical circuit, Wnt signaling, in order to promote proper regeneration. This ancient signaling circuit operates in all animals and controls many processes in development and disease, including tissue repair and cancer progression.

With head-facing wounds, the gene acts like a dimmer switch to dampen the Wnt pathway and promote head regeneration. When the head or tail of a planarian is cut off, Wnt is activated, turning on the gene, but only at head-facing wounds. In a feedback loop, notum then turns Wnt down low enough that it can no longer prevent a head from forming.

In tail-facing wounds, however, notum is not activated highly, a condition that promotes tail regrowth. It takes the worm about a week to regrow a head or tail.

Like the Wnt signaling pathway, notum is highly conserved throughout species, from sea anenomes to fruit flies to humans, but little is known about its roles in biology. Because both notum and the Wnt signaling pathway are so evolutionarily ancient, their interaction in planarians may indicate a relationship that is important in other animals as well.

“We anticipate that this phenomenon of feedback inhibition regulating the levels of Wnt activity will be seen broadly in other biological contexts,” Reddien says.

“Wnt signaling is so broadly studied and important in biology, including for tissue repair and regeneration. Notum isn’t really on the map for the broad roles Wnt signaling plays in tissue repair, but this work demonstrates the central role it can play.”

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