Title : The
heterotaxy gene
GALNT11 glycosylates
Notch to orchestrate cilia type and laterality
Abstract :
- Heterotaxy is a disorder of left-right body patterning, or laterality, that is associated with major congenital heart disease
- The aetiology and mechanisms underlying most cases of human hete rotaxy are poorly understood
- In vertebrates, laterality is initiated at the embryonic left-right organizer, where motile cilia generate leftward flow that is detected by immotile sensory cilia, which transduce flow into downstream asymmetric signals
- The mechanism that specifies these two cilia types remains unknown
- Here we show that the N-acetylgalactosamine-type O-glycosylation enzyme GALNT11 is crucial to such determination
- We previously identified GALNT11 as a candidate disease gene in a patient with hete rotaxy, and now demonstrate, in Xenopus tropicalis, that galnt11 activates Notch signalling
- GALNT11 O-glycosylates human NOTCH1 peptides in vitro, thereby supporting a mechanism of Notch activation either by increasing ADAM17-mediated ectodomain shedding of the Notch receptor or by modification of specific EGF repeats
- We further developed a quantitative live imaging technique for Xenopus left-right organizer cilia and show that Galnt11-mediated Notch1 signalling modulates the spatial distribution and ratio of motile and immotile cilia at the left-right organizer
- galnt11 or notch1 depletion increases the ratio of motile cilia at the expense of immotile cilia and produces a laterality defect reminiscent of loss of the ciliary sensor Pkd2
- By contrast, Notch overexpression decreases this ratio, mimicking the ciliopathy primary ciliary dyskinesia
- Together our data demonstrate that Galnt11 modifies Notch , establishing an essential balance between motile and immotile cilia at the left-right organizer to determine laterality, and reveal a novel mechanism for human hete rotaxy