Figure 7–34 A small set of transcription regulators can convert one differentiated cell type into another. in this experiment, (A) liver cells grown in culture were converted into (B) neuronal cells via the artificial expression of three nerve-specific transcription regulators. Both types of cells express an artificial red fluorescent protein, which is used to visualize them. this conversion involves the activation of many nerve-specific genes as well as the repression of many liver-specific genes. (from S. Marro et al., Cell Stem Cell 9:374–382, 2011. with permission from elsevier.)
Figure 7–33 The importance of combinatorial gene control for development. Combinations of a few transcription regulators can generate many cell types during development. in this simple, idealized scheme, a “decision” to make one of a pair of different transcription regulators (shown as numbered circles) is made after each cell division. Sensing its relative position in the embryo, the daughter cell toward the left side of the embryo is always induced to synthesize the even-numbered protein of each pair, while the daughter cell toward the right side of the embryo is induced to synthesize the odd-numbered protein. the production of each transcription regulator is assumed to be self-perpetuating once it has become initiated (see figure 7–39). in this way, through cell memory, the final combinatorial specification is built up step by step. in this purely hypothetical example, five different transcription regulators have created eight final cell types (G–n).
fy with Eyeless gene artifcially that would normally go on to form leg parts. Here, this abnormal gene expression change causes eye-like structures to develop in the legs (Figure 7–35).
Specialized Cell types Can Be experimentally reprogrammed to Become pluripotent Stem Cells
Manipulation of transcription regulators can also coax various differentiated cells to de-differentiate into pluripotent stem cells that are capable of giving rise to the different cell types in the body, much like the embryonic stem (ES) cells discussed in Chapter 22. When three specific transcription regulators are artificially expressed in cultured mouse fibroblasts, a number of cells become induced pluripotent stem cells (iPS cells)—cells that look and behave like the pluripotent ES cells that are derived from embryos (Figure 7–36). This approach has been adapted to produce iPS cells from a variety of specialized cell types, including cells taken from humans. Such human iPS cells can then be directed to generate a population of differentiated cells for use in the study or treatment of disease, as we discuss in Chapter 22.
Although it was once thought that cell differentiation was irreversible, it is now clear that by manipulating combinations of master transcription regulators, cell types and differentiation pathways can be readily altered.
Combinations of Master transcription regulators Specify Cell types by Controlling the expression of Many Genes
As we saw in the introduction of this chapter, different cell types of multicellular organisms differ enormously in the proteins and RNAs they express. For example, only muscle cells express special types of actin and myosin that form the contractile
Figure 7–35 Expression of the Drosophila Eyeless gene in precursor cells of the leg triggers the development of an eye on the leg. (A) Simplified diagrams showing the result when a fruit fly larva contains either the normally expressed Eyeless gene (left) or an Eyeless gene that is additionally expressed artificially in cells that normally give rise to leg tissue (right).
(B) photograph of an abnormal leg that contains a misplaced eye (see also figure 21–2). the transcription regulator was named eyeless because its inactivation in otherwise normal flies causes the loss of eyes. (B, courtesy of walter Gehring.)