PUBLICATION

A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling

Authors
Frikstad, K.M., Molinari, E., Thoresen, M., Ramsbottom, S.A., Hughes, F., Letteboer, S.J.F., Gilani, S., Schink, K.O., Stokke, T., Geimer, S., Pedersen, L.B., Giles, R.H., Akhmanova, A., Roepman, R., Sayer, J.A., Patzke, S.
ID
ZDB-PUB-190815-7
Date
2019
Source
Cell Reports   28: 1907-1922.e6 (Journal)
Registered Authors
Sayer, John A.
Keywords
CEP104, CSPP1, Hedgehog signaling, Joubert syndrome, MT plus end, centriolar satellites, ciliopathies, primary cilium
MeSH Terms
  • Retinal Pigment Epithelium/cytology
  • Retinal Pigment Epithelium/metabolism*
  • Ciliopathies/metabolism
  • Ciliopathies/pathology*
  • Animals
  • Hedgehog Proteins/genetics
  • Hedgehog Proteins/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Cilia/physiology*
  • Mutation
  • Cells, Cultured
  • Microtubule-Associated Proteins/genetics
  • Microtubule-Associated Proteins/metabolism*
  • Humans
  • Signal Transduction
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism
  • Cell Cycle Proteins/genetics
  • Cell Cycle Proteins/metabolism*
(all 21)
PubMed
31412255 Full text @ Cell Rep.
Abstract
CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. CEP104 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that cep104 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our in vivo and in vitro analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
AB + CRISPR1-cep104 + CRISPR2-cep104standard conditions10-13 somites
AB + CRISPR1-cep104 + CRISPR2-cep104standard conditionsLong-pec
AB + CRISPR1-cep104 + CRISPR2-cep104standard conditionsLong-pec
AB + CRISPR1-cep104 + CRISPR2-cep104standard conditionsLong-pec
AB + CRISPR1-cep104 + CRISPR2-cep104standard conditionsLong-pec
AB + MO1-cep104standard conditions10-13 somites
AB + MO1-cep104standard conditionsLong-pec
AB + MO1-cep104standard conditionsLong-pec
AB + MO1-cep104standard conditionsLong-pec
AB + MO1-cep104standard conditionsLong-pec
1 - 10 of 21
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
rw0TgTransgenic Insertion
    twu34TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      Human Disease Fish Conditions Evidence
      Joubert syndromeTAS
      1 - 1 of 1
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      Sequence Targeting Reagents
      Target Reagent Reagent Type
      cep104CRISPR1-cep104CRISPR
      cep104CRISPR2-cep104CRISPR
      cep104MO1-cep104MRPHLNO
      cep104MO2-cep104MRPHLNO
      1 - 4 of 4
      Show
      Fish
      Fish
      AB + CRISPR1-cep104 + CRISPR2-cep104
      AB + MO1-cep104
      AB + MO1-cep104 + MO2-cep104
      AB + MO2-cep104
      rw0Tg + CRISPR1-cep104 + CRISPR2-cep104
      rw0Tg + MO1-cep104
      twu34Tg + MO1-cep104
      1 - 7 of 7
      Show
      Antibodies
      Name Type Antigen Genes Isotypes Host Organism
      Ab1-cep104monoclonal
        		IgG2aMouse
        Ab4-gapdhmonoclonal
          		IgGRabbit
          1 - 2 of 2
          Show
          Orthology
          Gene Orthology
          cep104
          1 - 1 of 1
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          Engineered Foreign Genes
          Marker Marker Type Name
          EGFPEFGEGFP
          GFPEFGGFP
          1 - 2 of 2
          Show
          Mapping
          No data available
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          Citation
          Frikstad, K.M., Molinari, E., Thoresen, M., Ramsbottom, S.A., Hughes, F., Letteboer, S.J.F., Gilani, S., Schink, K.O., Stokke, T., Geimer, S., Pedersen, L.B., Giles, R.H., Akhmanova, A., Roepman, R., Sayer, J.A., Patzke, S. (2019) A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling. Cell Reports. 28:1907-1922.e6.