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Maintaining the differentiated state

Development obviously means more than initiating gene expression. For a cell to become committed to a particular phenotype, gene expression must be maintained. Evolution has resulted in four major pathways for maintaining differentiation once it has been initiated (see Figure 1).

Figure 1  Four ways of maintaining differentiation after the initial signal has been given. (A) The initial stimulus (1) activates enhancer 1, which stimulates the promoter (2) to transcribe the gene. The gene product (3) is a transcription factor, and one of its targets is enhancer 2 of its own gene (4). This activated enhancer can now stimulate the promoter (5) to make more of this protein. (B) Proteins such as those of the Trithorax group prevent nucleosomes from forming so that the gene remains accessible. (C) Autocrine stimulation of the differentiated state. The cell is stimulated to activate those genes that enable it to synthesize and bind its own stimulatory proteins. (D) Paracrine loop between two cells such that a paracrine factor from one cell stimulates the differentiated state of the second cell, and that differentiated state includes the secretion of a paracrine factor that maintains the first cell’s differentiated state.

(Click image to enlarge.)

1. The transcription factor whose gene is activated by a signal transduction cascade can bind to the enhancer of its own gene. In this way, once the transcription factor is made, its synthesis becomes independent of the signal that induced it originally. The MyoD transcription factor in muscle cells is produced in this manner.

2. A cell can stabilize its differentiation by synthesizing proteins that act on chromatin to keep genes accessible. Such proteins include the Trithorax family discussed in Chapter 2.

3. A cell can maintain its differentiation in an autocrine fashion. If differentiation is dependent on a particular signaling molecule, the cell can make both that signaling molecule and that molecule’s receptor. This produces a “community effect” (Grobstein 1955; Saxén and Wartiovaara 1966; Gurdon 1988), where the capacity to express a developmental potential exists only when a critical cell density of induced cells is present. In other words, once a group of cells has been induced, autocrine factors can sustain that induction and complete their differentiation.*

In Xenopus muscle development, this community effect is mediated through FGF signaling. Standley and colleagues (2001) have shown (1) that FGF signaling can simulate the community effect in isolated muscle precursor cells; (2) that the muscle precursor cells have the receptors for FGFs at the critical time; and (3) that the muscle precursor cells express FGFs at this time. It thus appears that part of the developmental program for Xenopus muscle cells is to make an FGF protein to which those same cells can also respond (i.e., an autocrine factor). This protein has to be present in sufficiently high density for the continuation of the processes leading to muscle development.

In sea urchins, the identity of a group of cells that become the ectoderm around the mouth is also coordinated in this manner. Here, a Nodal paracrine factor from one cell causes the phosphorylation of Smad2 transcription factor in the neighboring cell receiving the signal. This activated transcription factor causes the neighboring cell to also make and secrete a Nodal signal. This keeps all the cells in the field actively secreting Nodal (Bolouri and Davidson 2009).

4. A cell may interact with its neighboring cells such that each one stimulates the differentiation of the other, and part of each neighbor’s differentiated phenotype is the production of a paracrine factor that stimulates the other’s phenotype. This type of I-scratch-your-back-you-scratch-mine strategy is found in the neighboring cells of the developing vertebrate limb and insect segments. This technique can be used to generate two different types of cells next to one another (as it does in insect segments; see Chapter 6). Or this mechanism can be used to generate a single population of cells (if the signal is the same). If this is so, it will also generate a “community effect,” like the sea urchin example described for mechanism 3.

*Community effect is also extremely important in bacterial development. Here it is called “quorum sensing,” and it is critical in permitting emergent phenotypes such as light production, biofilm formation, invasiveness, and virulence. These phenotypes are expressed only in groups of bacteria and not in individuals. Each bacterium makes a small amount of a diffusible autocrine inducer that will induce the phenotype only at relatively high concentrations (see Zhu et al. 2002; Podbielski and Kreikemeyer 2004).

Literature Cited

Bolouri, H. and E. H. Davidson. 2009. The gene regulatory network basis of “community effect,” and analysis of a sea urchin embryo example. Biochim. Biophys. Acta Gene Reg. Mech. 1789(4): 363–374.

Grobstein, C. 1955. Tissue disaggregation in relation to determination and stability of cell type. Ann. NY Acad. Sci. 60: 1095–1107.

Gurdon, J. B. 1988. A community effect in animal development. Nature 336: 772–774.

Podbielski, A. and B. Kreikemeyer 2004. Cell density-dependent regulation: Basic principles and effects on the virulence of Gram-positive cocci. Int. J. Infect. Dis. 8: 81–95.

Saxén, L. and J. Wartiovaara 1966. Cell contact and cell adhesion during tissue organization. Int. J. Cancer 1: 271–290.

Standley, H. J., A. M. Zorn and J. B. Gurdon. 2001. eFGF and its mode of action in the community effect during Xenopus myogenesis. Development 128: 1347–1357.

Zhu, J., M. B. Miller, R. E. Vance, B. L. Bassler and J. J. Mekalanos. 2002. Quorum-sensing regulators control virulence gene expression in Vibrio cholerae. Proc. Natl. Acad. Sci. USA 99: 3129–3134.

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