Craniofacial malformations are common structural birth defects and usually associate with abnormal development of pharyngeal arches. Although some microRNAs have been found to be implicated in chondrogenesis in vitro, few have been shown to be essential for cartilage and bone development at the whole organism level. In this study, we report that mir92a is highly enriched in the chondrogenic progenitors and that its inactivation results in loss of pharyngeal cartilage elements due to poor proliferation, impaired differentiation, and unsustainable survival of chondrogenic progenitors. The Bmp antagonist gene noggin3 (nog3) is a direct target of mir92a. Inactivation of mir92a stabilizes nog3 mRNA, leading to repression of Bmp signaling and abnormal behaviors of chondrogenic progenitors. In contrast, ectopic expression of mir92a duplex decreases nog3 mRNA levels and, as a result, derepresses Bmp signaling and promotes cell apoptosis. Therefore, mir92a acts to maintain Bmp activity during pharyngeal cartilage formation by targeting nog3.

As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish. Furthermore, the polyglutamine (polyQ)-expanded ATX-3 retains enhanced interaction and deubiquitination catalytic activity to p53 and causes more severe p53-dependent neurodegeneration in zebrafish brains and in the substantia nigra pars compacta (SNpc) or striatum of a transgenic SCA3 mouse model. Our findings identify a novel molecular link between ATX-3 and p53-mediated cell death and provide an explanation for the direct involvement of p53 in SCA3 disease pathogenesis.

Microtubules function in TGF-β signalling by facilitating the cytoplasmic trafficking of internalized receptors and the nucleocytoplasmic shuttling of Smads. However, nothing is known about whether actin filaments are required for these processes. Here we report that zebrafish actin-bundling protein fscn1a is highly expressed in mesendodermal precursors and its expression is directly regulated by the TGF-β superfamily member Nodal. Knockdown or knockout of fscn1a leads to a reduction of Nodal signal transduction and endoderm formation in zebrafish embryos. Fscn1 specifically interacts with TGF-β family type I receptors, and its depletion disrupts the association between receptors and actin filaments and sequesters the internalized receptors into clathrin-coated vesicles. Therefore, Fscn1 acts as a molecular linker between TGF-β family type I receptors and the actin filaments to promote the trafficking of internalized receptors from clathrin-coated vesicles to early endosomes during zebrafish endoderm formation.