PUBLICATION

mtor Haploinsufficiency Ameliorates Renal Cysts and Cilia Abnormality in Adult Zebrafish tmem67 Mutants

Authors
Zhu, P., Qiu, Q., Harris, P.C., Xu, X., Lin, X.
ID
ZDB-PUB-210213-13
Date
2021
Source
Journal of the American Society of Nephrology : JASN   32(4): 822-836 (Journal)
Registered Authors
Lin, Xueying, Xu, Xiaolei, Zhu, Ping
Keywords
genetics and development, molecular genetics, optical clearing, polycystic kidney disease
MeSH Terms
none
PubMed
33574160 Full text @ J. Am. Soc. Nephrol.
Abstract
Background Although zebrafish embryos have been used to study ciliogenesis and model polycystic kidney disease (PKD), adult zebrafish remain unexplored.
Methods Transcription activator-like effector nucleases (TALEN) technology was used to generate mutant for tmem67, the homolog of the mammalian causative gene for Meckel syndrome type 3 (MKS3). Classic 2D and optical-clearing 3D imaging of an isolated adult zebrafish kidney were used to examine cystic and ciliary phenotypes. A hypomorphic mtor strain or rapamycin was used to inhibit mTOR activity.
Results Adult tmem67 zebrafish developed progressive mesonephric cysts that share conserved features of mammalian cystogenesis, including a switch of cyst origin with age and an increase in proliferation of cyst-lining epithelial cells. The mutants had shorter and fewer distal single cilia and greater numbers of multiciliated cells (MCCs). Absence of a single cilium preceded cystogenesis, and expansion of MCCs occurred after pronephric cyst formation and was inversely correlated with the severity of renal cysts in young adult zebrafish, suggesting a primary defect and an adaptive action, respectively. Finally, the mutants exhibited hyperactive mTOR signaling. mTOR inhibition ameliorated renal cysts in both the embryonic and adult zebrafish models; however, it only rescued ciliary abnormalities in the adult mutants.
Conclusions Adult zebrafish tmem67 mutants offer a new vertebrate model for renal cystic diseases, in which cilia morphology can be analyzed at a single-nephron resolution and mTOR inhibition proves to be a candidate therapeutic strategy.
Genes / Markers
Marker Marker Type Name
cc2d2aGENEcoiled-coil and C2 domain containing 2A
cep290GENEcentrosomal protein 290
cimap1bGENEciliary microtubule associated protein 1B
gapdhGENEglyceraldehyde-3-phosphate dehydrogenase
mks1GENEMKS transition zone complex subunit 1
mtorGENEmechanistic target of rapamycin kinase
tmem67GENEtransmembrane protein 67
1 - 7 of 7
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Figures
No images available
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
xu015GtTransgenic Insertion
xu095
    		Insertion
    1 - 2 of 2
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    tmem67TALEN1-tmem67TALEN
    1 - 1 of 1
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    Fish
    No data available
    Antibodies
    Orthology
    Engineered Foreign Genes
    Marker Marker Type Name
    GFPEFGGFP
    1 - 1 of 1
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    Mapping
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    Citation
    Zhu, P., Qiu, Q., Harris, P.C., Xu, X., Lin, X. (2021) mtor Haploinsufficiency Ameliorates Renal Cysts and Cilia Abnormality in Adult Zebrafish tmem67 Mutants. Journal of the American Society of Nephrology : JASN. 32(4):822-836.