The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality

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Abstract
The O-glycosylation enzyme Galnt11 has an important role in heterotaxy, a disorder of left–right body patterning or laterality: Galnt11 modulates Notch signalling which alters cilia types at the embryonic left–right organizer, therefore determining laterality. A failure to establish correct left–right body patterning during embryogenesis can cause heterotaxy, a rare birth defect involving major congenital heart disease. Mustafa Khokha and colleagues have characterized the role of the GalNAc-type O-glycosylation enzyme, product of the GALNT11 gene associated with human heterotaxy. They found that GALNT11 modulates both Notch signalling and the spatial distribution and ratio of motile and immotile cilia at the embryonic left–right organizer to determine laterality. The study identifies a novel mechanism for human heterotaxy. Heterotaxy is a disorder of left–right body patterning, or laterality, that is associated with major congenital heart disease1. The aetiology and mechanisms underlying most cases of human heterotaxy 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 signals2,3,4,5,6. 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 heterotaxy7, 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 heterotaxy.

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