title: Foxn4 promotes gene expression required for the formation of multiple motile cilia.
abstract: Multiciliated cell (MCC) differentiation involves extensive organelle biogenesis required to extend hundreds of motile cilia. Key transcriptional regulators known to drive the gene expression required for this organelle biogenesis are activated by the related coiled-coil proteins Multicilin and Gemc1. Here we identify foxn4 as a new downstream target of Multicilin required for MCC differentiation in Xenopus skin. When Foxn4 activity is inhibited in Xenopus embryos, MCCs show transient ciliogenesis defects similar to those seen in mutants of Foxj1, a known key regulator of genes required for motile ciliation. RNAseq analysis indicates that Foxn4 co-activates some Foxj1 target genes strongly and many Foxj1 targets weakly. ChIPseq suggests that whereas Foxn4 and Foxj1 frequently bind to different targets at distal enhancers, they largely bind together at MCC gene promoters. Consistent with this co-regulation, cilia extension by MCCs is more severely compromised in foxn4 and foxj1 double mutants than in single mutants. In contrast to Foxj1, Foxn4 is not required to extend a single motile cilium by cells involved in left-right patterning. These results indicate that Foxn4 complements Foxj1 transcriptionally during MCC differentiation, thereby shaping the levels of gene expression required for the timely and complete biogenesis of multiple motile cilia.
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Evan P
authors.initials: EP
authors.lastname: Campbell
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ian K
authors.initials: IK
authors.lastname: Quigley
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA kintner@salk.edu.
authors.forename: Chris
authors.identifier: 0000-0002-8288-0296
authors.initials: C
authors.lastname: Kintner
mesh_terms: D000818:Animals; D064652:Basal Bodies / Q000502:physiology; D064113:CRISPR-Cas Systems / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002923:Cilia / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D060172:Morpholinos / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D012867:Skin / Q000196:embryology*; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C490956:FOXJ1 protein, Xenopus; C518899:FOXN4 protein, Xenopus; D051858:Forkhead Transcription Factors; C551026:GMNC protein, Xenopus; D060172:Morpholinos; D009419:Nerve Tissue Proteins; D029867:Xenopus Proteins; C571015:multicilin, Xenopus
keywords: Cilia; Foxj1; Foxn4; Multiciliate cells; Xenopus laevis