How does the 1.5-fold increase in gene dosage on chromosome 21 lead to the many phenotypes of Down syndrome? New work shows that this pleiotropy can be traced back to two genes — DSCR1 and DYRK1A— that together inhibit a family of transcription factors that have a role in many aspects of vertebrate development.
Mice in which components of NFAT signalling have been genetically inactivated have phenotypic features that resemble human Down syndrome. Prompted by these observations, Grabtree, Graef and colleagues examined the critical Down syndrome region on chromosome 21 for genes that might downregulate NFAT. One such gene is DSCR1, which is overexpressed in Down syndrome human fetuses. DSCR1 is an inhibitor of the phosphatase calcineurin, which controls the rate of nuclear import of the calcium-dependent components of NFAT transcription complexes (NFATc proteins).
Having examined the 25–30 other candidates in this region of chromosome 21, the authors came across DYRK1A. It encodes a serine/threonine kinase that primes substrates for phosphorylation by GSK3, which in the case of NFATc proteins leads to their inactivation and removal from the nucleus. Once they confirmed the DYRK1A-mediated reduction of NFAT transcriptional activity, the authors made mouse transgenic lines in which both DSCR1 and DYRK1A were overexpressed. They report that 1.5- to 3-fold increased levels of expression were sufficient to cause some of the Down syndrome developmental defects.
The effects of a modest — 1.5 fold — increase in the expression levels of DSCR1 and DYRK1A are likely to be exaggerated by the fact that members of the NFAT family autoregulate. So to better predict the outcome of NFAT signalling the authors developed a mathematical model. One of the predictions states that NFAT targets might completely fail to be expressed because activation of their promoters might require a certain NFAT threshold level. Another prediction is that the NFAT regulatory circuit might not be equally stable in different tissues, resulting in stronger phenotypic effects in some tissues than others.
This work elegantly shows that many of the developmental phenotypes of Down syndrome might be a consequence of perturbing the NFAT regulatory circuit, in response to increased dosage of DSCR1 and DYRK1A. It also has wider implications — if other diseases are also caused by specific weaknesses in genetic regulatory circuits then understanding and exploiting these weaknesses can have therapeutic potential.