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Cell-cell interactions in cell fate determination in Caenorhabditis elegans

What is the role of induction in cell fate determination?

C. elegans has similar advantages to Drosophila as a system for the study of development: the exploitation of the power of genetics. Furthermore the fates of each and every cell during development to the adult are known (Sulston et al., 1983). Thus, cell fate studies can be done very precisely. We shall examine the determination of pharyngeal fate development as an example of the kinds of elegant developmental analyses that are possible with C. elegans..

The first cleavage division generates a large anterior AB blastomere and a smaller posterior P1 blastomere (Evans et al., 1994, Fig. 1). Descendants of both AB and P1 produce pharyngeal cells during development. However, they differ in their potential to produce these cells. P1 has an intrinsic ability to produce posterior pharyngeal cells when it is isolated from AB. However, AB descendants only produce anterior pharyngeal cells as a result of interactions with P1 descendants, in a process that requires maternal expression of the glp-1 gene.

The GLP-1 protein is a transmembrane protein that is thought to function as a receptor for extracellular signals. In embryos from homozygous glp-1 mutant mothers, P1 produces pharyngeal cells, but AB does not, indicating that a glp-1-dependent signaling event is necessary for AB to produce pharyngeal cells. This observation demonstrates how genetic tools can be used to answer questions that would otherwise require manipulations of embryos.

The larger AB blastomere divides to produce ABa and ABp, whereas P1 divides to yield EMS and P2. Of the two products of P1 division, only EMS retains the ability to produce posterior pharyngeal cells. The cells at this stage are situated in the egg case such that P2 is adjacent to ABp and not ABa (see Fig. 1). Thus, P2 and ABp can engage in cell-cell interactions that require glp-1.

At the next division, EMS divides to produce E and MS. The MS cell engages in an inductive interaction that causes descendents of ABa to form anterior pharynx. This interaction also requires glp-1 . Because GLP-1 is a thought to be receptor protein, it should be produced in descendants of the anterior blastomere, which are the targets of these glp-1-dependent interactions.

Although the glp-1 mRNA is present in both the oocyte and embryo, the GLP-1 protein is not synthesized in oocytes. Is its synthesis generalized, or is it restricted to the anterior blastomeres? The immunolocalization results shown in Figure 2 reveal that the protein is strictly restricted to the anterior blastomeres. This localization occurs in spite of the uniform distribution of the mRNA. Thus, the mRNA is subject to spatially-restricted translation.

Because of the frequent involvement of 3' UTRs on translational regulation, Evans et al. tested whether the 3' UTR of glp-1 is responsible for its regulation. A reporter construct was made that had a -galactosidase coding sequence and nuclear localization signal located upstream of a glp-1 3' UTR. (The nuclear localization signal allowed for the -gal to accumulate in nuclei and be more readily detectable.) A control reporter that lacked the glp-1 3' UTR was also used. RNA was synthesized in vitro from either construct and injected into the germline.

As shown in Figure 5 (Evans et al., 1994), embryos derived from animals injected with control RNA had lacZ staining throughout the embryo, whereas those derived from animals injected with lacZglp-1 RNA had -gal staining only in anterior blastomeres. However, the RNA itself was evenly distributed within the embryos (Fig. 6). Thus, the glp-1 3' UTR is sufficient to restrict translation to the anterior blastomeres. A deletion analysis was conducted to identify the elements in the 3' UTR that regulate glp-1 translation. As shown in Table 1, a 125 nt element at the 3' end of the UTR is necessary and sufficient for temporal regulation, whereas a 61 nucleotide region in the middle of the 3' UTR is required for spatial regulation. (See also Fig. 5G-5I.) These results indicate that the localization of GLP-1 protein is a consequence of translational regulation of glp-1 mRNA.

The role of induction in determination of cell fate in C. elegans has only recently been appreciated. It had previously been thought that cell fate was entirely a consequence of intrinsic differences among cells due to localization of determinants. These inductive interactions operate at the level of single cells, whereas inductive interactions in higher organisms function at the tissue level.

Learning Objectives

  • Diagram cleavage to the 8-cell stage. Label each cell and place on your diagram the interactions that are necessary for the formation of the anterior pharynx.
  • What is the role of GLP-1?
  • What is the phenotype of embryos derived from homozygous glp-1 mothers?
  • How is synthesis of GLP-1 regulated? Describe experimental evidence.

Digging Deeper:

Recent Literature

Han, M. 1997. Gut reaction to Wnt signaling in worms. Cell 90: 581-584.

Thorpe, C.J., Schlesinger, A., Carter, J.C. and Bowerman, B. 1997. Wnt signaling polarizes an early C. elegans blastomere to distinguish endoderm from mesoderm. Cell 90: 695-705.

Rocheleau, C.E., Downs, W.D., Lin, R., Wittmann, C., Bei, Y., Cha, Y.-H., Ali, M., Priess, J.R. and Mello, C.C. 1997. Wnt signaling and an APC-related gene specify endoderm in early C. elegans embryos. Cell 90: 707-716.


Evans, T.C., S.L. Crittendon, V. Kodoyianni and J. Kimble. 1994. Translational control of maternal glp-1 mRNA establishes an asymmetry in the C. elegans embryo. Cell 77: 183-194.

Sulston, J.E., E. Schierenberg, J.G. White and J.N. Thomson. 1983. The embryonic cell lineage of the nematode Caenorhabditis elegans. Develop. Biol. 100: 64-119.

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Leon Browder & Laurie Iten (Ed.) Dynamic Development
Last revised Tuesday, July 14, 1998