Gerhardt, C. | bioRxiv Science

bioRxiv2020

Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein Rpgrip1l governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of Rpgrip1l.

cell biology↗

bioRxiv2020

Gain-of-function mutation in Gli3 causes ventricular septal defects

Ventricular septal defects (VSDs) are developmental disorders, characterised by a gap in the septum between the right and the left ventricle, that lead to life-threatening heart defects. At present, the only curative treatment of VSDs is surgical closure. Since these surgeries comprise several severe risks, the development of alternative therapies against VSDs is urgently needed. To develop such therapies, the current knowledge of the molecular factors and mechanisms underlying VSDs has to be increased. Based on our previous data, we analysed the relevance of the HH signalling pathway mediator GLI3 in ventricular septum (VS) formation. GLI3 functions as both a transcriptional activator (GLI3-A) and repressor (GLI3-R). By analysing two different mouse Gli3 mutants, we revealed that the lack of GLI3-A with simultaneous presence of GLI3-R impairs cilia-mediated PDGFR signalling causing reduced cell proliferation and in consequence the development of VSDs. Moreover, we showed that the rescue of PDGFR signalling restores cell proliferation. Since VSDs are also appear in humans with comparable gain-of-function mutations in GLI3, our findings propose activators of PDGFR signalling as potential agents against the development of VSDs. SUMMARYThe article reports how a gain-of-function mutation of Gli3 causes ventricular septal defects and paves the way for therapies tackling these congenital heart defects.

developmental biology↗