Trends in Genetics
OpinionDownstream of Otx2, or how to get a head
Section snippets
Otx2 has multiple functions in brain development
Otx2 has a number of different roles in the early development of the brain. The first of these is in the specification and migration of a group of endodermal cells, the anterior visceral endoderm (AVE) 6, 7, 8. The AVE acts as a ‘head organizer’, lining the ectoderm that is fated to form anterior brain and inducing Otx2 expression in these cells. Otx2 expression is subsequently maintained in an anterior-to-posterior (anteroposterior) gradient within the forebrain and midbrain.
Otx2 also has a
Otx2 controls multiple downstream target genes
How does Otx2 regulate such a vast array of developmental steps? The answer presumably lies with the control (activation or repression) of its downstream target genes. This control could be exerted directly, with the OTX2 protein binding to the promoter or enhancer of the target gene. In this case, no intermediate steps of transcription and translation would be required. Alternatively, OTX2 might control genes indirectly, by modulating the expression of a second gene that would then activate or
Most Otx2 target genes fall into one of six functional categories
Reviewing these Otx2 target genes as a group has allowed us to make some interesting observations about the way in which Otx2 functions. The first of these is that, although the target genes are highly divergent in sequence, they can be fitted into six functional groups (Fig. 2), the most notable of which are outlined below.
Otx2 and the circadian cycle
The circadian rhythm is a highly conserved timing mechanism allowing the anticipation of daily environmental changes (i.e. light–dark cycles). It consists of a relatively simple molecular loop involving transcriptional and translational feedbacks between a relatively small number of genes (reviewed in Ref. 27). An essential component of this loop is encoded by the clock gene, which together with the BMAL1 protein activates transcription of other circadian components and circadian responsive
Possible models for the function of Otx2
Two opposing hypotheses can be envisaged as to how Otx2 functions to determine anterior fate. In the first (Fig. 3a), Otx2 directly controls a large number of target genes, the products of which do not affect the activity of other genes but define the identity of the cell; for example, by fulfilling a structural or metabolic function. The opposite of this would be where Otx2 directly controls the expression of only a relatively small number of genes, such as transcription factors and signaling
Acknowledgements
We thank A. Morgan, T. King and S. Webb for their critical reading of the manuscript and for their helpful comments.
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