FBRSL1, a gene causative for a congenital malformation syndrome, is important for cardiac and craniofacial development in Xenopus laevis
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Congenital malformation syndromes affect a significant number of new-borns, yet many of these syndromes are not well understood. One of these rare, uncharacterized conditions is the FBRSL1-associated syndrome, which is caused by de novo truncating variants in the Fibrosin-like 1 (FBRSL1) gene. This gene encodes different isoforms, with the long variants containing an AUTS2 domain in the C-terminal part, whereas the short N-terminal isoforms include an alternative exon 3. Patient mutations are located in the N-terminal part of the gene, in exon 2 or exon 3, and individuals with these variants suffer from cardiac and craniofacial defects, in addition to other malformations. Consequently, using a Fbrsl1 knockdown model in Xenopus laevis, the present work demonstrates that Fbrsl1 plays an important role in heart and neural crest (NC) cell development. Consistent with the location of the patient variants, rescue experiments with different human FBRSL1 isoforms revealed the importance of a short N-terminal FBRSL1 isoform in these embryonic processes. In the context of heart development, we show that fbrsl1 morphant embryos exhibit severely hypoplastic hearts. In addition, our data indicate that Fbrsl1 is essential for the development of the first heart field. In contrast, second heart field formation and induction of cardiac progenitor cells appear normal in Fbrsl1 knockdown embryos. Concerning craniofacial development, we demonstrate that Fbrsl1 is dispensable for induction and early migration of NC cells. However, the protein is important for later stages of NC development as we observe a gradual loss of marker gene expression during late migration and differentiation stages. Notably, the defects observed are likely independent of the ability of NC cells to migrate, as migration parameters of Fbrsl1-depleted cells were normal compared to control cells. The developmental defects at tadpole stages correlate with increased p53 and cleaved caspase-3 levels in morphant embryos, and analysis of NC cell tissue confirmed increased apoptosis in this cell population. Moreover, inhibition of p53 partially restores the craniofacial defects of Fbrsl1 knockdown embryos. This implies that increased apoptosis in cranial NC cells could underlie the loss of marker gene expression at tadpole stages and the craniofacial malformations. Consistent with a pathological mechanism involving apoptosis, Fbrsl1-depleted embryos exhibit exon 4 skipping in murine double minute 2 (mdm2), a major repressor of p53. Fbrsl1 may directly affect mRNA splicing of mdm2, as we found interaction of the protein with the Splicing factor 3B subunit 1 (SF3B1). Given that defects in the splicing machinery frequently trigger apoptosis, resulting in craniofacial and heart defects, an important function of FBRSL1 in mRNA splicing would be consistent with our observations. In addition, we provide evidence for a function of FBRSL1 in transcriptional regulation. We show that FBRSL1 localizes upstream of coding genes and associates with the transcription factor Yin Yang 1 (YY1). Additionally, FBRSL1 is important for the transcription of bromodomain and PHD finger containing protein 1 (BRPF1) and lysine acetyltransferase 6 a (KAT6A). These two proteins are part of a chromatin acetylase complex that controls the expression of genes during various embryonic processes. Thus, developmental defects caused by FBRSL1 loss of function are probably also linked to its role in transcriptional regulation. Collectively, we provide new insights into the function of FBRSL1 in embryonic development and the pathogenesis of the complex FBRSL1-associated congenital malformation syndrome.
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Issued: 2025-11-06
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FB17:Biologie
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en
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FBRSL1Xenopus laeviscongenital malformation syndromemolekulare Embryologie
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Gerstner, Sarah: FBRSL1, a gene causative for a congenital malformation syndrome, is important for cardiac and craniofacial development in Xenopus laevis. : 2025-11-06.
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