PUBLICATION

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system

Authors
Noble, A.R., Masek, M., Hofmann, C., Cuoco, A., Rusterholz, T.D.S., Özkoc, H., Greter, N.R., Phelps, I.G., Vladimirov, N., Kollmorgen, S., Stoeckli, E., Bachmann-Gagescu, R.
ID
ZDB-PUB-241015-6
Date
2024
Source
Biology Open   13(11): (Journal)
Registered Authors
Bachmann-Gagescu, Ruxandra, Masek, Markus, Phelps, Ian, Rusterholz, Tamara
Keywords
Cc2d2a, Central nervous system, Joubert syndrome, Primary cilia, Talpid3, Zebrafish
MeSH Terms
  • Animals
  • Eye Abnormalities*/genetics
  • Transcriptome
  • Gene Expression Profiling
  • Retina*/abnormalities
  • Retina*/metabolism
  • Cerebellum*/abnormalities
  • Cerebellum*/metabolism
  • Signal Transduction
  • Zebrafish*/genetics
  • Kidney Diseases, Cystic*/genetics
  • Cilia/genetics
  • Cilia/metabolism
  • Abnormalities, Multiple*/genetics
  • Central Nervous System/abnormalities
  • Central Nervous System/metabolism
  • Phenotype
  • Disease Models, Animal*
  • Mutation*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
(all 21)
PubMed
39400299 Full text @ Biol. Open
Abstract
Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. In order to identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2aw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain, however do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
bz6TgTransgenic Insertion
    fh297
      		Point Mutation
      i264
        		Insertion
        ka742
          		Small Deletion
          vu12TgTransgenic Insertion
            w38
              		Point Mutation
              zh506
                		Small Deletion
                zh510
                  		Indel
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  inpp5eCRISPR2-inpp5eCRISPR
                  inpp5eCRISPR3-inpp5eCRISPR
                  1 - 2 of 2
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                  Fish
                  No data available
                  Antibodies
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  GCaMPEFGGCaMP
                  TagRFPEFGTagRFP
                  1 - 3 of 3
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                  Mapping
                  No data available
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                  Citation
                  Noble, A.R., Masek, M., Hofmann, C., Cuoco, A., Rusterholz, T.D.S., Özkoc, H., Greter, N.R., Phelps, I.G., Vladimirov, N., Kollmorgen, S., Stoeckli, E., Bachmann-Gagescu, R. (2024) Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system. Biology Open. 13(11):.