Increased dosage of DSCR1 and DYRK1A destabilizes NFAT regulation and accounts for Down syndrome phenotypes
Trisomy 21 results in Down syndrome (DS), but little is known about how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes of DS. Studies of patients with partial trisomy 21 have defined a “DS critical region” (DSCR) on chromosome 21q. The DSCR contains 25-30 genes including DSCR1, which encodes a calcineurin (Cn)/NFAT inhibitor. We noted that mice harboring mutations of the four genes encoding NFATc transcription factors, individually and in various combinations, exhibit many of the phenotypic features of DS, such as craniofacial shortening, learning and memory defects, increased sociability, hypotonia, aganglionic megacolon and structural heart defects. Interestingly, the DSCR encodes another NFAT regulator, DYRK1a. We found that this nuclear kinase blocks NFAT activity by priming it for glycogen synthase kinase-3 (GSK-3) phosphorylation, resulting in rapid nuclear export. To experimentally test the synergistic effects of DYRK1a and DSCR1 overexpression, we made double transgenic mice that have cardiac malformations at E13.5 similar to those seen in DS mouse models and NFATc1-/- mice. Mathematical modeling of the NFAT pathway, which includes positive and negative feedback loops, predicts that a 1.5-fold increase in DSCR1 and DYRK1a levels will reduce NFAT activity and alter the expression of target genes. Consistent with this model, we documented enhanced NFATc phosphorylation in brain and heart from DS fetuses relative to age-matched controls. We propose that the 1.5-fold increase in gene dosage of DSCR1 and DYRK1A in trisomy 21 cooperatively destabilizes a regulatory circuit that leads to reduced NFAT activity and causes many of the features of DS. More generally, our proposal suggests that destabilization of regulatory circuits, involving only a small number of genes, may account for the phenotypic features of segmental aneuploidies.