Trends in Genetics
Volume 17, Issue 11, 1 November 2001, Pages 633-636
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Downstream of Otx2, or how to get a head

https://doi.org/10.1016/S0168-9525(01)02418-0Get rights and content

Abstract

Otx2 is a member of a highly conserved family of homeodomain-containing transcription factors that function in early brain development. Recent studies have identified a significant number of target genes downstream of Otx2, allowing us to address the question of how it fulfils its diverse developmental roles. Interestingly, many of these target genes are not transcription factors or signaling molecules, and they probably have no direct affect on gene expression. Furthermore, there is evidence that Otx2 coordinates the activity of unrelated genes that have overlapping functions, and that it does so directly without intermediate transcriptional or signaling activity.

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.

References (31)

  • C.B Green

    The circadian gene Clock is restricted to the anterior neural plate early in development and is regulated by the neural inducer noggin and the transcription factor Otx2

    Mech. Dev.

    (2001)
  • F Fukamauchi

    Abnormal behavior and neurotransmissions of tenascin gene knockout mouse

    Biochem. Biophys. Res. Commun.

    (1996)
  • J.D Glass

    Polysialylated neural cell adhesion molecule modulates photic signaling in the mouse suprachiasmatic nucleus

    Neurosci. Lett.

    (2000)
  • F Hirth et al.

    Conserved genetic programs in insect and mammalian brain development

    BioEssays

    (1999)
  • S.L Ang

    A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain

    Development

    (1996)
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