Regulation of early Xenopus development by the PIAS genes

Abstract

Originally identified as cytokine inhibitors, protein inhibitors of activated STAT (PIAS) are shown to regulate activities of a plethora of proteins and influence diverse processes such as immune response, cancer formation, and cell cycle progression. However, the roles of PIAS during vertebrate embryogenesis are less understood. In this study, we report isolation and initial characterization of all four PIAS genes from Xenopus laevis. The Xenopus PIAS genes are expressed throughout early development and have overlapping and distinct expression patterns, with for example high levels of PIAS2 in the notochord and strong expression of PIAS4 in the neural and neural crest derivatives. Overexpression of PIAS disrupts mesoderm induction and impairs body axis formation. PIAS proteins have differential ability to regulate signals from the growth factors activin, bone morphogenetic protein 4 (BMP4), and Wnt8. Our data suggest that Xenopus PIAS play important roles in mesodermal induction and patterning during early frog development.

PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome

“…32 Additional cases (showing almost the same phenotype) that either partially overlapped or did not include this 113.5 kb SRO region suggest that part of the phenotypic features could be explained by a 'position effect' or by additional genes close to this SRO (Figure 2). Therefore we hypothesize that the interval from TLE2 to CREB3L3 within 19p13.3, a highly conserved region among different species 33,34 with a rich content in haploinsufficient genes (with 16/55 with a high likelihood of being haploinsufficient), 35 as a critical region responsible for most clinical features. Additional genes that may contribute to clinical features are (from centromere to telomere): EEF2, DAPK3, NMRK2, ATCAY and NFIC, among others (Figure 2), which are involved in cognitive impairment, 36 regulation of myogenic differentiation, 37 apoptosis and transcriptional regulation of canonical Wnt/β-catenin signaling, 38 and autosomal recessive Cayman cerebrallar ataxia, 39 respectively.…”

“…The potential relevance of this~1.1 Mb interval from TLE2 to CREB3L3 (that includes the SRO) is supported by its highly conserved nature in all vertebrates, from fish to mammals. 33,34 Further support underlining the importance of this highly conserved region and its contribution to the clinical features in patients with 19p13.3 deletion/duplications is given by their haploinsuffiency (HI) score. HI score (defined by Huang and colleagues, 2010) 35 ranges from 0 to 100, where 0 means highly haploinsufficient and 100 not haploinsufficient.…”

“…We speculate that very large deletions and The specific mechanism of how PIAS4 or other RNF proteins may be involved in macro/microcephaly is unknown, but PIAS4 is highly conserved from zebrafish to mammals. 33,34 One hypothesized mechanism is disruption of AR-mediated transcription, which is a common feature of PIAS-like proteins. 52 A second hypothesis is disruption of bone morphogenetic protein-signaling pathways, as the RING domain of PIAS4 is involved in its suppression.…”

Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor

“…This fact may have a direct relation between PIAS4 and the brain size during the Xenopus embryonic development. 38 We also report here a 16-year-old girl with a PIAS4 nonsense var- and its potential contribution to the phenotype.…”

“…in vivo experiments in Xenopus demonstrated that PIAS4 is highly expressed in neural cells and neural crest derivatives, including the brain. This fact may have a direct relation between PIAS4 and the brain size during the Xenopus embryonic development …”