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Origins of licensing control

Organ development requires precise regulation of both the total number and the different types of cells. Much is known about how each process is controlled, but new light has been shed on how the two are linked.

From fertilization to maturity, a single set of genetic information must be accurately passed on to each daughter cell during the cell cycle; the mechanism involved is known as ‘replication licensing’. At the same time, specialized cells and organs use unique combinations of genes, which are switched on or off by factors that control gene transcription, and this process — cell differentiation — determines the types of cell that will arise. These two processes are expected to be tightly integrated during development in order to generate organs of the correct size. On pages 745 and 749 of this issue, Wittbrodt et al.1 and Kessel et al.2 provide further insights into the molecular interactions between regulation of the cell cycle and regulation of cellular differentiation.

Replication licensing involves the sequential assembly of components of a replication complex onto the regions from which DNA replication begins3. At the heart of this regulatory machinery are families of proteins that include the ‘origin recognition complex’ and the ‘minichromosome maintenance complex’. But before the latter complex can bind, two other proteins — Cdc6 and Cdt1 — must be in place. And the formation of the replication complex itself is regulated both positively and negatively during the cell cycle so that replication occurs only once. A protein known as geminin is involved in inhibiting replication licensing4,5 — it interacts with Cdt1 and so prevents the assembly of the minichromosome maintenance complex (Fig. 1).

Figure 1: Regulation of cell proliferation and differentiation by Six and Hox proteins.
figure1

a, Cdt1 is an essential component of the replication complex, which mediates proliferation. b, The interaction of geminin with Cdt1 inhibits assembly of the minichromosome maintenance complex (MCM), so proliferation cannot occur unless geminin is degraded. c, Kessel and colleagues2 have found that Hox can displace geminin from Cdt1, thereby allowing proliferation to proceed. Geminin displaces Hox from its target genes and/or can interact with polycomb proteins to influence Hox activity. d, Wittbrodt and colleagues1 show that an interaction between Six and geminin can displace geminin from Cdt1 and so induce proliferation. Geminin antagonizes Six3 transcriptional activity but does not interfere with its ability to bind DNA. Geminin regulates cell differentiation by directly interacting with Six and Hox.

Kessel and colleagues2 have identified a strong interaction between geminin and transcription factors of the Hox and polycomb protein families, which are essential for embryonic patterning and the specification of tissues and organs6,7. The interaction between Hox and geminin can displace geminin from Cdt1, and so promotes DNA replication and cell proliferation (Fig. 1). Using a series of approaches in chick embryos, Kessel and colleagues found that geminin interacts with polycomb to modify the region in which the Hoxb9 gene is expressed. The authors also suggest that geminin behaves in vivo like a polycomb protein — it inhibits Hox gene activation. Because polycomb factors are likely to be recruited in response to specific epigenetic markers that influence gene expression, there may be other components involved in this inhibitory mechanism7.

Meanwhile, Wittbrodt and colleagues1 investigated the functions of the Six family of transcription factors, which are linked to development and proliferation in certain tissues. Six3 and Six6, the most closely related members of the Six gene family in vertebrates, are required for the development of the eye8,9. When Wittbrodt and colleagues searched for factors that interact physically with Six3, they found geminin — so just as geminin can bind Hox, it can also interact with Six3. Six3 seems to promote cell proliferation by displacing geminin from Cdt1 (Fig. 1). Using the retina as a model system, Wittbrodt and colleagues show that inhibiting the function of geminin (loss-of-function), similar to increasing the function of Six3 (gain-of-function), promotes cell proliferation and so increases retina size. Geminin gain-of-function, like Six3 loss-of-function, can be restored by overexpressing Six3. Six3 and Six6 might also control cell proliferation by directly regulating specific genes that control growth8,9. This study, therefore, also provides the first evidence that members of the Six family can function in both a transcription-dependent and -independent manner by regulating replication-licensing events through geminin and Cdt1.

So a role for geminin in controlling cell proliferation is emerging. But how does it control cell differentiation10? The present studies suggest that it might do so by interacting directly with genes such as Six and Hox. In this regard, the new results1,2 support different notions. Wittbrodt and colleagues1 show that geminin antagonizes the function of Six3 in gene transcription without interfering with its DNA-binding activity. On the other hand, Kessel and colleagues2 suggest that geminin can antagonize Hox function by displacing Hox from the genes that it targets and/or by regulating Hox gene expression by interacting with specific polycomb gene pathways. Perhaps the discrepancy reflects the differences between transcription factors?

So the results of both groups provide an intriguing additional molecular link between the control of cell differentiation and the control of proliferation — they support a general model in which genes that are involved in regulating development also control cell proliferation by directly inhibiting the interaction of geminin with Cdt1. Geminin is present only when the nucleus divides during the cell cycle11, so it will be of particular interest to find out whether this cell-cycle-specific expression of geminin is involved in determining the cell type. Also, to what extent might this principle apply to other proteins that are similar to Hox and Six, and to other classes of transcription factor?

References

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