PMID: 24226769

 

    Legend: Gene, Sites

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

Abstract :
  1. Heterotaxy is a disorder of left-right body patterning, or laterality, that is associated with major congenital heart disease
  2. The aetiology and mechanisms underlying most cases of human hete rotaxy are poorly understood
  3. 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
  4. The mechanism that specifies these two cilia types remains unknown
  5. Here we show that the N-acetylgalactosamine-type O-glycosylation enzyme GALNT11 is crucial to such determination
  6. 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
  7. 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
  8. 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
  9. 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
  10. By contrast, Notch overexpression decreases this ratio, mimicking the ciliopathy primary ciliary dyskinesia
  11. 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
Output (sent_index, trigger, protein, sugar, site):
  • 0. glycosylates, , Notch, -, -
  • 7. O-glycosylates, , -, -, peptides
Output(Part-Of) (sent_index, protein, site):
  • 7. NOTCH1, peptides
*Output_Site_Fusion* (sent_index, protein, sugar, site):

 

 

Protein NCBI ID SENTENCE INDEX
448197 1
Heterotaxy 448197 1
GALNT11 448751 0,6,7
hete 7547 2,6,11
Pkd2 100038156 9
galnt11 448751 6,9
Notch receptor 100037842 7
heterotaxy 448197 0
Galnt11 448751 8,11
ADAM17 100492947 7
Notch 100037842 0,6,7,10,11