The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry.
Vertebrate left-right (LR) asymmetry originates at a transient left-right organizer (LRO), a ciliated structure where cilia play a crucial role in breaking symmetry. However, much remains unknown about the choreography of cilia biogenesis and resorption at this organ. We recently identified a mutation affecting NEK2, a member of the NIMA-like serine-threonine kinase family, in a patient with congenital heart disease associated with abnormal LR development. Here, we report how Nek2 acts through cilia to influence LR patterning. Both overexpression and knockdown of nek2 in Xenopus result in abnormal LR development and reduction of LRO cilia count and motility, phenotypes that are modified by interaction with the Hippo signaling pathway. nek2 knockdown leads to a centriole defect at the LRO, consistent with the known role of Nek2 in centriole separation. Nek2 overexpression results in premature ciliary resorption in cultured cells dependent on function of the tubulin deacetylase Hdac6. Finally, we provide evidence that the known interaction between Nek2 and Nup98, a nucleoporin that localizes to the ciliary base, is important for regulating cilium resorption. Together, these data show that Nek2 is a switch balancing ciliogenesis and resorption in the development of LR asymmetry.
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, Fitkin 426, New Haven, CT 06520, USA.
S Joseph
SJ
Endicott
Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, Fitkin 426, New Haven, CT 06520, USA.
Basudha
B
Basu
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, Fitkin 426, New Haven, CT 06520, USA Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, Fitkin 426, New Haven, CT 06520, USA.
Mustafa
M
Khokha
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, Fitkin 426, New Haven, CT 06520, USA Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, Fitkin 426, New Haven, CT 06520, USA martina.brueckner@yale.edu.
Martina
M
Brueckner
D000818:Animals; D019521:Body Patterning; D002502:Centrioles / Q000378:metabolism; D002923:Cilia / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D000072379:NIMA-Related Kinases; D028861:Nuclear Pore Complex Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000502:physiology*; D000097577:Homeobox Protein PITX2
D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072379:NIMA-Related Kinases; D028861:Nuclear Pore Complex Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D029867:Xenopus Proteins; D000097577:Homeobox Protein PITX2; C495108:DAND5 protein, human; C558728:Nup98 protein, Xenopus; C490316:NEK2 protein, Xenopus; C490315:Nek2B protein, Xenopus; C089441:NEK2 protein, human; C499033:Hdac6 protein, mouse
Cilia; Congenital heart disease; Left-right asymmetry; Nek2; Nucleoporin