| Popis: |
Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) Syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function forRBM8A/Y14that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay. How perturbing a general mRNA-processing factor causes the selective TAR Syndrome phenotypes remains unknown. Here, we connect zebrafishrbm8aperturbation to early hematopoietic defects via attenuated non-canonical Wnt/Planar Cell Polarity (PCP) signaling that controls developmental cell arrangements. In hypomorphicrbm8azebrafish, we observe a significant reduction ofcd41-positive thrombocytes.rbm8a-mutant zebrafish embryos accumulate mRNAs with individual retained introns, a hallmark of defective nonsense-mediated decay; affected mRNAs include transcripts for non-canonical Wnt/PCP pathway components. We establish thatrbm8a-mutant embryos show convergent extension defects and that reducedrbm8afunction interacts with perturbations in non-canonical Wnt/PCP pathway genes wnt5b,wnt11f2,fzd7a, andvangl2. Using live-imaging, we found reducedrbm8afunction impairs the architecture of the lateral plate mesoderm (LPM) that forms hematopoietic, cardiovascular, kidney, and forelimb skeleton progenitors as affected in TAR Syndrome. Both mutants forrbm8aand for the PCP genevangl2feature impaired expression of early hematopoietic/endothelial genes includingrunx1and the megakaryocyte regulatorgfi1aa. Together, our data propose aberrant LPM patterning and hematopoietic defects as possible consequence of attenuated non-canonical Wnt/PCP signaling upon reducedrbm8afunction. These results link TAR Syndrome to a potential LPM origin and developmental mechanism. |
