Humans, Fruit Flies Trace Key Ability to Properly Form Tissues to Common, Ancient Ancestor

In a discovery that not only helps inform the molecular basis of animal regeneration, University of Utah medical researchers have also resolved a major mystery in the evolution of a key molecular pathway needed by all animals -- from humans to fruit flies to tiny worms -- for the early development and later maintenance of adult tissues.

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Oct 22, 2009 12:00 PM

SALT LAKE CITY—In a discovery that not only helps inform the molecular basis of animal regeneration, University of Utah medical researchers have also resolved a major mystery in the evolution of a key molecular pathway needed by all animals – from humans to fruit flies to tiny worms – for the early development and later maintenance of adult tissues.

In a study published online this week in the journal Science, researchers led by Alejandro Sánchez Alvarado, Ph.D., professor of neurobiology and anatomy at the U of U School of Medicine, show that all animals, including humans, inherited the basic molecular mechanism for early tissue development and maintenance from a common ancestor that likely lived more than a half-billion years ago.

The mystery revolved around the interaction between a molecular signaling pathway called Hedgehog (Hh), and cilia, which are tiny cellular appendages used by cells for functions ranging from motility to chemical sensation.  

The Hh signaling pathway was first discovered in fruit flies (drosophila), where it was found to play a key role in instructing embryonic cells to form a normal body plan. This pathway is critical for embryo development in both vertebrates (animals with backbones) and invertebrates (those without backbones), because in its absence, cells would assemble chaotically and embryos would develop improperly.

However, there is a major discrepancy in how the functions of the Hh pathway are carried out in vertebrates, including humans, and invertebrates such as fruit flies, according to Sánchez Alvarado, also an investigator with the Howard Hughes Medical Institute. For cells to communicate with each other using deeply evolutionarily conserved signaling pathways like Hh, they rely on transduction mechanisms, a process by which a cell converts one kind of signal or stimulus into another. In people, the signaling provided by the Hh pathway is mediated by cilia, and thus only functions properly when cilia are present. Fruit flies, on the other hand, don’t have cilia in most of their cells, yet their Hh pathway functions just fine. This perplexing diversity in the way animals transduce Hh signaling has puzzled developmental biologists for years.

“It wasn’t clear why there was a difference between vertebrates and invertebrates regarding Hh and cilia,” Sánchez Alvarado said. “But we knew the core components of the signaling mechanism were conserved in both fruit flies and mammals.”

To study this inconsistency, Sánchez Alvarado turned to a tiny worm that was a new model for investigating the issue, the planarian. Planarians have an uncanny ability to regenerate – an entire worm can be regenerated from a small fragment removed from the flank of the animal. Like the fruit fly, planarians are invertebrates, but, unlike fruit flies, they have an abundance of cilia.

Using a technique called RNA interference, Sánchez Alvarado and his team silenced (or disabled) the genes that form cilia in planarians. The genes targeted for silencing are known to play essential roles in mediating Hh signaling in mammals. Sánchez Alvarado and his research team found that cilia formation was severely disrupted, yet the hedgehog pathway’s ability to guide cells during development functioned normally. This led to a conclusion that had escaped scientists for years: the genes used by mammals to mediate Hh signaling must have had first an ancestral role in the function of cilia, but through eons of evolution and natural selection, individual species must have modified for their own purposes the relationship between the Hh pathway and cilia.

“In evolutionary terms, the relationship between cilia and Hh signaling isn’t new. It may, in fact, date back to the common ancestor for which there is no fossil record yet, but probably lived 800 million to 1 billion years ago,” Sánchez Alvarado said. “Thus, it appears that a key aspect of the mechanism that enables us and other animals to form properly developed tissues was in place a long time ago.” Still, he added, “we do not know why the need for cilia was retained in humans”

The work also shows a central role for Hh signaling in animal regeneration. The study showed that the Hh pathway can modulate the proliferation of stem cells essential for regeneration.  Loss of Hh results in a marked depression of stem cell proliferation, while excess Hh signaling results in overproliferation of these cells. These results are reminiscent of what has been observed in mammals and underscore the evolutionarily conserved nature of this signaling pathway among animals.

The researchers also demonstrate that Hh signaling helps animals determine anterior (head) and posterior (tail) ends during the regeneration of missing body parts. “How does the worm know which end to regenerate? Clearly, the Hh pathway is centrally involved in this decision,” Sánchez Alvarado said. It does so by regulating the activity of a second signaling pathway known as the Wnt/-catenin pathway. When the Hh pathway is inhibited, animals display a reduction of Wnt signaling, which results in an inability to regenerate posterior ends (tails).  Conversely, overactivation of Hh leads to an increase in Wnt signaling, which causes tails to grow at both anterior and posterior ends.

“Our work not only defines a hierarchy of signaling pathways that informs in fundamental ways the molecular basis of animal regeneration, but also provides an important example of how the study of planarians can expand our understanding of central aspects of evolutionary and developmental biology not easily resolved with traditional model systems such as flies and mice,” concluded Sánchez Alvarado.

Postdoctoral researchers Jochen C. Rink and Kyle A. Gurley are the study’s first authors, and graduate student Sarah A. Elliot is co-author.

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