divide, which is the hallmark feature of cell renewal.
Studies have shown that the intercellular communication, particularly that between cells residing in the niche, coupled with signaling factors, regulate the differentiation process of stem cells. In this scenario, a combination of conditions will induce stem cells at the distal tip to either continuously undergo mitosis or enter the differentiation process. Early experiments showed that the deletion of the distal tip cell or mutations induced in specific genes expressed in distal tip cells result in the premature entry into meiosis, indicating a loss of stem-cell identity. On the other hand, another protein, GLP-1, is expressed in distal tip cells and blocks their entry into meiosis, thus allowing the continuous division of the germ cells.
Factors That Control the Proliferation and Differentiation of Stem Cells in C. elegans
Cell-cell signaling serves as a common mechanism for establishing cell fate in animal development. In this scenario, signals are transmitted at specific stages of development or at particular phases of the cell lineage, resulting in the selection of a precise fate for a particular cell. It is also possible for a cell to detect multiple cues from its extracellular environment and thus the cell should be capable of discerning which signals it should initially respond to. Certain developmental changes in animals are strongly linked to specific stages of the cell cycle, whereas others are not. It is therefore essential that the target cell is cognizant of various temporal cues in order to appropriately progress through its developmental process.
One of the most extensively studied components of C. elegans is the Wnt signaling pathway that primarily controls development, either by maintaining cell renewal or allowing differentiation of stem cells. Wnt glycoproteins have the capability of binding to transmembrane protein receptors known as Frizzled. Niches in the C. elegans gonad thus possess Wnt gradients that regulate the number of stem cells that proliferate and differentiate within the gonad. Investigations using C. elegans have provided information on how a niche cell is generated. Distal tip cells are produced when a pair of somatic cells serving as gonad precursors undergo asymmetric cell division. Each precursor cell goes through this particular type of division according to the distal-proximal organizational axis; the daughter cells of the distal end thus generate more distal tip cells. Experiments involving mutations that affect this form of asymmetric cell division result in the disruption of its cellular organization, wherein both daughter cells become members of the proximal end of the gonad. Previous reports have described axis-related mutations in the genes pop-1, sys-3, and β-catenin, which are members of the Wnt signaling pathway that acts as the regulatory component of cells responsible for maintaining the distal-proximal organizational axis. Other earlier studies have shown that mutations in the mes-1 gene result in the unequal division of C. elegans stem cells, which results in a loss of polarity based on the distal-proximal axis, ultimately resulting in the cell differentiation.
C. elegans has also served as a model organism for studies involving cell induction mechanisms other than the Wnt signaling pathway. Studies indicate that extracellular signals serve as cues for precursor cells to develop into their specific fates. For example, the HOM-C transcription factors mab-5 and lin-39 are differentially expressed along the anteroposterior axis of vulval precursor cells of C. elegans, resulting in the development of the vulva. Mutation and induction assays have shown that these two transcription factors work in an antagonistic fashion that allows or prevents vulval precursor cells to act in response to neighboring anchor cells of the nematode gonad. Fibroblast growth factor and its corresponding receptor also play major roles in the establishment of the organization axis of vulval precursor cells.
The subsequent differentiation of these precursor cells results in myoblasts or muscle cells that assist in the egg-laying process of C. elegans. Pumilio (PUF) proteins pertain to a conserved family of RNA-binding proteins that regulate the translation, maintenance, and localization of various target messenger RNAs (mRNAs). A wide range of PUF proteins are involved in the development and maintenance of the C. elegans germline. For example, FBF-1 and FBF-2 are PUF proteins that are responsible in sex determination in the nematode. By inhibiting the activity of the protein fem-3, FBF-1 and FBF-2 assist in the determination whether the germ cells would proceed toward spermatogenesis or oogenesis, thus establishing the sex of the organism. On the other hand, PUF-5/6/7 pertains to another PUF protein complex that regulates the production of oocytes.
Reprogramming Cell Fate in C. elegans
Aside from inducing proliferative cells to undergo differentiation into specific cell types, C. elegans has also been used as a model organism for the study of redirecting cell fate. The process of dedifferentiation pertains to the reversal of a cell state, from a fully differentiated condition to an undifferentiated state, which is strongly characterized by features of high rates of proliferation and multipotency. Cancer stem cells, also known as tumor-initiating cells, possess this feature of dedifferentiation, thus allowing them to enter the cell cycle and produce more daughter cells that would further populate a specific region of the body, resulting in a tumor.
In C. elegans, differentiation of germ cells occurs at the distal end of the gonad. These germ cells are induced to enter meiosis and migrate toward the proximal end of the gonad, where more specialized cells are located. During this process, various regulators are secreted, including RNA-binding proteins the regulate self-renewal or differentiation of the germ cells. However, in the presence of other factors such as inhibitors of the MAPK signaling pathway and in the absence of RNA-binding proteins, fully differentiated cells are induced to dedifferentiate and enter mitosis, which is a common feature of undifferentiated stem cells. The application of RNA interference (RNAi) specific to downstream effectors of the MAPK signaling pathway can also stimulate C. elegans spermatocytes to undergo dedifferentiation, facilitating their entry into meiosis.
Previous studies have shown that these extracellular regulators comprise the molecular circuitry of cell fate reprogramming in the C. elegans, which are also highly likely to occur in other animal species, including humans. The PUF protein PUF-8 plays several roles in the development of the C. elegans germline. Inhibition assays targeting PUF-8 have shown that in the absence of or when the activity of PUF-8 is impaired through mutation or interference, primary spermatocytes undergo dedifferentiation and then proceed with their reentry into the mitotic cell cycle.
C. elegans as a Model for Cancer Stem Cells
Asymmetric cell division is an essential cellular mechanism that allows an organism to maintain a sufficient number of cells of each type. In C. elegans, asymmetric cell division allows the production of two daughter cells that have the potential to proceed toward their own distinct path. One cell fate for nematode stem cells involves the distal tip, which is a region that consists of cells that constantly divide, thus generating more cells in its pool. The other cell fate is that of the differentiating cell and progresses into a specific germ cell that determines the sex of the organism.
Other than its role in development, asymmetric cell division has also been associated with the production of cancer stem cells. Previous studies have suggested that tumors might have arisen from a subpopulation of stem cells that are capable of self-renewal. This incessant expansion of cells is a hallmark of both normal stem cells and cancer cells and thus it is possible that the same mechanism of asymmetric cell division could be pursued for the control of cancer progression. The detailed events of asymmetric cell division may also be used as targets of novel pharmaceutical products that aim to prevent the further proliferation of cancer stem cells. Current studies are investigating various extracellular and intracellular signals that regulate the processes of self-renewal and differentiation of stem cells in C. elegans, with the hope of gathering more information on the components and steps involved in each mechanism.
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