PUBLICATION
SBDSR126T rescues survival of sbds-/- zebrafish in a dose-dependent manner independently of Tp53
- Authors
- Oyarbide, U., Shah, A.N., Staton, M., Snyderman, M., Sapra, A., Calo, E., Corey, S.J.
- ID
- ZDB-PUB-231011-55
- Date
- 2023
- Source
- Life science alliance 6(12): (Journal)
- Registered Authors
- Corey, Seth, Oyarbide, Usua, Snyderman, Matt
- Keywords
- none
- MeSH Terms
-
- Animals
- Bone Marrow Diseases*/genetics
- Bone Marrow Diseases*/metabolism
- Bone Marrow Diseases*/pathology
- Female
- Lipomatosis*/genetics
- Lipomatosis*/metabolism
- Lipomatosis*/pathology
- Neutropenia*
- Nuclear Proteins/genetics
- Proteins/genetics
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- PubMed
- 37816584 Full text @ Life Sci Alliance
Citation
Oyarbide, U., Shah, A.N., Staton, M., Snyderman, M., Sapra, A., Calo, E., Corey, S.J. (2023) SBDSR126T rescues survival of sbds-/- zebrafish in a dose-dependent manner independently of Tp53. Life science alliance. 6(12):.
Abstract
Defects in ribosomal biogenesis profoundly affect organismal development and cellular function, and these ribosomopathies produce a variety of phenotypes. One ribosomopathy, Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, pancreatic exocrine insufficiency, and skeletal anomalies. SDS results from biallelic mutations in SBDS, which encodes a ribosome assembly factor. Some individuals express a missense mutation, SBDSR126T , along with the common K62X mutation. We reported that the sbds-null zebrafish phenocopies much of SDS. We further showed activation of Tp53-dependent pathways before the fish died during the larval stage. Here, we expressed SBDSR126T as a transgene in the sbds-/- background. We showed that one copy of the SBDSR126T transgene permitted the establishment of maternal zygotic sbds-null fish which produced defective embryos with cdkn1a up-regulation, a Tp53 target involved in cell cycle arrest. None survived beyond 3 dpf. However, two copies of the transgene resulted in normal development and lifespan. Surprisingly, neutropenia persisted. The surviving fish displayed suppression of female sex differentiation, a stress response in zebrafish. To evaluate the role of Tp53 in the pathogenesis of sbds-/- fish phenotype, we bred the fish with a DNA binding deficient allele, tp53M214K Expression of the loss-of-function tp53M214K did not rescue neutropenia or survival in sbds-null zebrafish. Increased expression of cdkn1a was abrogated in the tp53M214K/M214K;sbds-/- fish. We conclude that the amount of SBDSR126T protein is important for development, inactivation of Tp53 fails to rescue neutropenia or survival in the sbds-null background, and cdkn1a up-regulation was dependent on WT tp53 We hypothesize that additional pathways are involved in the pathophysiology of SDS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping