Homeobox genes: eyeing the clock

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Homeobox proteins can work as effectors of a cellular clock that regulates the timing of retinal cell differentiation.

Homeobox genes are best known for their crucial role in early animal development. New work by Decembrini et al. now provides evidence that homeobox proteins can work as effectors of a cellular clock during retinal cell differentiation.

Differentiation of the progenitor precursor cells into retinal neurons requires the activation of homeobox genes according to a precise, evolutionarily conserved time schedule. To gain insight into the mechanisms that guarantee the tight temporal coordination between cell birth and cell-fate specification, Decembrini and colleagues studied the spatio-temporal expression patterns of three homeobox genes that are essential to drive the differention of photoreceptor cells (Xotx5b) or bipolar cells (Xotx2 and Xvsx1) in the Xenopus retina.

In the early progenitor cells, Xotx5b, Xotx2 and Xvsx1 are transcribed but not translated, indicating the existence of some post-transcriptional regulatory mechanism. This translational inhibition is due to the presence of cis-regulatory sequences in the 3' UTRs of these genes, which might be targets for regulatory microRNAs — a computational prediction identified several such putative targets. Regardless of the mechanism of inhibition, there is a striking correlation between the translational onset of each homeobox message and the generation of the retinal cells in which the event takes place.

Interestingly, to be efficiently translated, the mRNAs of Xotx5b, Xotx2 and Xvsx1 require cell-cycle progression. In fact, blocking cell-cycle progression, for example, by hydroxyurea or Xgadd-45, results in a reduced translation of the homeobox mRNAs and a decreased differentiation of photoreceptors and bipolar cells.

Is this reduction in retinal cells a direct consequence of the low levels of the homeobox proteins? Indeed, this seems to be the case, because the overexpression of Xotx5b or Xvsx1 coding sequences can reverse the effects of the cell-cycle inhibitor, increasing the population of photoreceptors or bipolar cells, respectively. By contrast, transcripts that also contain the 3' UTR are much less effective in rescuing retinal cell differentiation.

So, these results seem to indicate the existence of a cell-cycle-dependent cellular clock that sets the time when retinal cells are generated; the homeobox proteins are likely to function as downstream effectors of this cellular clock, because their ectopic expression can bypass the blockade of the cell cycle.

The authors shortened the cell cycle of late progenitor cells by transfecting regulators such as E2F or cdk2/cyclinA2 to show that the retinal cellular clock might function by measuring cell-cycle length rather than the time spent cycling. They suggest that the lengthening of the cell cycle that is observed during retinogenesis would allow the progenitors to translate enough homeobox proteins to differentiate further. The translational inhibitors, which are likely to be part of the clock machinery, as well as the molecular nature of the other clock components, remain to be identified.

Francesca Pentimalli

References

Decembrini, S. et al. Timing the generation of distinct retinal cells by homeobox proteins. PLoS Biol. 4, 1562-1571 (2006) | Article |