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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
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Home | Pregnancy Timeline | News Alerts |News Archive Dec 5, 2013

 

Adult cells in the C. elegans pharynx (left) change into intestine-like cells (middle) with only a flip of a single switch, as revealed by fluorescent molecules specific for these cells.

Image Credit: Misty R. Riddle







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Changing cell types by flipping a single switch

With few exceptions, cells don't change type once they have become specialized — a heart cell, for example, won't suddenly become a brain cell. However, new findings by researchers at UC Santa Barbara have identified a method for changing one cell type into another in a process called forced transdifferentiation.

Their work appears today in the journal Development.

With C. elegans as the animal model, lead author Misty Riddle, a Ph.D. student in the Rothman Lab, used transcription factor ELT-7 to change the roundworm's pharynx cells into intestine cells in a single-step process.


Every cell has the genetic potential to become any kind of cell. However, the cell's history and the signals it receives changes the transcription factors it contains and thus determines what kind of cell it will become.

A transcription factor is a protein that causes genes to turn on.


"This discovery is quite surprising because it was previously thought that only early embryonic cells could be coaxed into changing their identity this readily," Riddle said. "The committed cells that we switched are completely remodeled and reprogrammed in every way that we tested."

Switching one cell type into another to replace lost or damaged tissue is a major focus of regenerative medicine. The stumbling block is that cells are very resistant to changing their identity once they've committed to a specific kind.

"Our discovery means it may become possible to create a tissue or organ of one type directly out of one of another type," says Joel Rothman, professor in UCSB's Department of Molecular, Cellular and Developmental Biology, who heads the lab.

Riddle and her colleagues challenged all C. elegans cells to make the switch to intestine, but only the pharynx cells were able to do so. "We asked skin cells, muscles, neurons to change but found that only the cells in the pharynx were able to transform," Riddle explained. "So this brings up some big questions. Why aren't other cells changing their identities? What is special about the cells in the pharynx that allow them to change their identity into intestine?

"Since C. elegans is such an incredible model system we can really tackle these questions," she continued. "By knocking down certain genes and manipulating the animal, we can begin to better understand the conditions under which skin cells and muscles cells might change their identities. That will help us figure out what is special about the cells in the pharynx."

Previous studies in the Rothman lab revealed the cascade of transcription factors required for the proper development of the C. elegans intestine. Used in the later stage of intestine development, ELT-7 continues to be expressed for the life of the animal and has important functions not only in gut development but also in gut function.


This study is revolutionary in that researchers have clearly demonstrated that cells are not limited to their original identities.


"Think of them as different rooms in a house," Riddle explains. "Like cells, different rooms in your house have different structures and functions. Changing the function of a room is likely to be easier if the structures are similar, say, turning a bedroom into a living room or vice versa. But changing the bathroom into a living room presents a bigger challenge.

"Just as some rooms in a house are more easily converted to others, some cell types may be more easily coaxed into changing their identity to another specific type. This doesn't seem to depend on the relatedness of the cells in terms of when they were born or how closely related they are in their lineage."

Maybe the heart cell can become a brain cell after all.


As demonstrated by another important finding in the UCSB study, the cells remodeled themselves in a continuous process; there were stages in the remodeling process during which the identity of the cell was mixed.


"Going back to the home remodeling example," Riddle said, "the couch and television were added to the bedroom before the bed and dresser were removed."

Rothman adds: "The key importance of our finding is that we have observed cells undergoing a process of morphing in which one specialized cell type is converted into another of an entirely different type.

"This means that it may be possible to turn any cell into any other cell in a direct conversion. In terms of our understanding of biological constraints over cell identity, we've shown a barrier that we believed absolutely prevents cells from switching their identity does not exist. It may one day be possible to switch an entire organ from one kind to another."

Abstract
Summary
Terminally differentiated post-mitotic cells are generally considered irreversibly developmentally locked, i.e. incapable of being reprogrammed in vivo into entirely different cell types. We found that brief expression of a single transcription factor, the ELT-7 GATA factor, can convert the identity of fully differentiated, highly specialized non-endodermal cells of the pharynx into fully differentiated intestinal cells in intact larvae and adult Caenorhabditis elegans. Stable expression of intestine-specific molecular markers parallels loss of markers for the original differentiated pharynx state; hence, there is no apparent requirement for a dedifferentiated intermediate during the transdifferentiation process. Based on high-resolution morphological characteristics, the transdifferentiated cells become remodeled to resemble typical intestinal cells at the level of both the cell surface and internal organelles. Thus, post-mitotic cells, though terminally differentiated, remain plastic to transdifferentiation across germ layer lineage boundaries and can be remodeled to adopt the characteristics of a new cell identity without removal of inhibitory factors. Our findings establish a simple model to investigate how cell context influences forced transdifferentiation of mature cells.

Authors
Misty R. Riddle1, Abraham Weintraub1,‡, Ken C. Q. Nguyen2, David H. Hall2 and Joel H. Rothman1,3,*

- Author Affiliations
1 Department of Molecular, Cellular and Developmental Biology, and Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA.
2 Center for C. elegans Anatomy, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3 School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand.
+ Author Notes

↵‡ Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

↵* Author for correspondence (rothman@lifesci.ucsb.edu)