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Adult stem cell regulator?

A protein related to RNAi machinery helps control dividing neoblasts

By | November 28, 2005

A protein related to RNA interference (RNAi) machinery appears to regulate how the adult stem cells differentiate in planarians, scientists reported in the November 25Science. Relatives of the protein, SMEDWI-2, are highly conserved across plants, yeast, and humans, and additional studies of the protein's structure and functioning could shed light on how adult stem cells are regulated in general, according to senior author Alejandro Sanchez Alvarado.

"While many regulators of embryonic stem cells have been identified, the same cannot be said for adult somatic stem cells, where our understanding of their maintenance and regulation are not as well worked out," Sanchez Alvarado, based at the University of Utah in Salt Lake City, told The Scientist.

Members of the highly conserved PIWI/Argonaute proteins are key components of RNAi pathways. They also are linked to germline stem cells, but "little to nothing is known about the role of PIWI in adult somatic stem cells," Sanchez Alvarado said. Using in situ hybridization and reverse transcription polymerase chain reactions (RT-PCR), Sanchez Alvarado and his colleagues found that, in planarians, PIWI family members smedwi-1 and smedwi-2 are expressed specifically in dividing neoblasts, or adult somatic stem cells, suggesting the genes might help regulate those cells.

To pinpoint genes linked to regeneration, the researchers had used RNAi screens in the planarianSchmidtea mediterranea. Regeneration in planarians requires neoblasts to divide into differentiated progeny. While silencing smedwi-1 did not cause any obvious defects, Sanchez Alvarado and his colleagues -- in particular Peter Reddien, now at the Whitehead Institute -- found inhibiting smedwi-2 made planarians incapable of regeneration after at least eight days. Also, tissue in front of the photoreceptors regressed, likely because such tissue lacks dividing neoblasts and is normally replaced by neoblast progeny during homeostasis, the authors note.

Inhibiting smedwi-2 did not knock out neoblasts, however. Fluorescence-activated cell sorting analyses indicated neoblasts remained present in smedwi-2-silenced planarians, and in situ hybridization showed some neoblasts expressed cell division marker cyclinB, demonstrating they were still proliferating.

However, after inhibiting smedwi-2 with RNAi, the researchers saw that bromodeoxyuridine-labeled neoblasts entered the epidermis sooner than normal and were grossly misshapen. This suggests that smedwi-2 ensures that dividing neoblasts generate progeny that can replace cells during homeostasis and missing tissues during regeneration, they report.

The findings focus attention on another dimension in understanding genetic regulation of stem cells: the competence of stem cell progeny to perform differentiated functions, Richard Behringer at the University of Texas at Houston, who did not participate in this study, told The Scientist. This function is separate from the typical tasks of renewal and maintenance, he noted.

Future experiments could investigate the gene expression profiles in smedwi-2-inhibited planarians to assess the protein's downstream targets, Sanchez Alvarado said. Studies could also test whether over-expressing genes in epithelial cells or neoblasts might rescue regeneration in smedwi-2-inhibited planarians, Brigitte Galliot at the University of Geneva, not a co-author, told The Scientist.

Additional studies could look at what effects, if any, inhibiting smedwi-2 has on other cell types, Elly Tanaka at the Max Planck Institute in Dresden, who did not participate in this study, told The Scientist. Sanchez Alvarado suggested inhibiting smedwi-1 may have affected neoblast progeny cells the researchers did not spot, although he noted that another PIWI protein may also compensate for smedwi-1's inhibition.

Phil Newmark at the University of Illinois at Urbana-Champaign is currently developing antibodies against planarian PIWI members, Sanchez Alvarado noted, which could help reveal where smedwi-2 is localized within the cell and how it works, perhaps through interacting with RNAs. "SMEDWI-2 does have PAZ and PIWI domains, which are known to bind small RNAs such as siRNAs and cleave mRNAs, respectively," Sanchez Alvarado said.

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