Trends in Genetics
Volume 20, Issue 1, January 2004, Pages 4-8
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The ins and outs of transcriptional control: nucleocytoplasmic shuttling in development and disease

https://doi.org/10.1016/j.tig.2003.11.007Get rights and content

Abstract

Recent findings relating to SOX transcription factors indicate that defects in organogenesis can be caused not only by impairment of the biochemical properties of transcription factors but also, in some cases, by deficient nuclear import. In addition, experimentally interfering with the nuclear export signals of some SOX factors has now been found to cause developmental defects. Controlling the balance of nuclear import and export might be a common means by which transcription factor activity can be regulated during development, and defects in these processes might underlie a broader spectrum of inherited developmental disorders.

Section snippets

Of great import

Mutations in the sex determining region on the Y chromosome (SRY) account for ∼10% of all cases of XY sex reversal in humans 12, 13. The only functional domain of the SRY protein known to be conserved between species is the high-mobility group (HMG) domain, a 79-amino acid region involved in the specific binding and sharp bending of DNA 14, 15. The majority of SRY mutations resulting in XY sex reversal occur within the HMG domain, predominantly causing defects in binding to target DNA sequences

Nuclear family

In the dozen years since the discovery of SRY, a gene family has sprung up around it – the SOX or SRY-like HMG box genes [22]. These genes, as the name implies, encode proteins that contain an HMG domain related to that of SRY (usually with sequence identity at the amino acid level of >50% [23]. All of the well-characterized SOX genes, like their founding member SRY, are involved in embryonic development. SOX9 is involved in chondrocyte formation during skeletal development 24, 25 and is

In through the out door

Intuitively, a mechanism by which a transcription factor can be shunted into the nucleus would seem to be a basic requirement for its function once it is produced in the cell cytoplasm. It is perhaps not surprising that interference with this process could cause disruptions to proper cellular development. However, the story is not this simple. Recent data [10] suggest that active mechanisms for nuclear export and import are required for SOX9 function. Prior to sexual differentiation, SOX9

Conclusion

Active, continuous shuttling between nucleus and cytoplasm might prove to be important to the function of the majority of SOX proteins in development, and their malfunction in human disease. Certainly the importance of nuclear import and export of a range of SOX proteins can be tested experimentally using targeted mutation strategies in mice. In broader terms, the regulation of nucleocytoplasmic shuttling is clearly another level of control over how, when and where transcription factors operate

Acknowledgements

We thank Josephine Bowles, Megan Wilson and Annemiek Beverdam of the Koopman laboratory for critical reading of the manuscript. J.M.S. is the recipient of an Australian Postgraduate Award and a supplementary scholarship from the Institute for Molecular Bioscience. P.A.K. is a Professorial Research Fellow of the Australian Research Council.

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