PUBLICATION
Missense and nonsense mutations of the zebrafish hcfc1a gene result in contrasting mTor and radial glial phenotypes
- Authors
- Castro, V.L., Paz, D., Virrueta, V., Estevao, I.L., Grajeda, B.I., Ellis, C.C., Quintana, A.M.
- ID
- ZDB-PUB-230223-48
- Date
- 2023
- Source
- Gene 864: 147290 (Journal)
- Registered Authors
- Quintana, Anita
- Keywords
- 14-3-3 αβ, Akt/mTOR, HCFC1, asxl1, neural development
- MeSH Terms
-
- Animals
- Codon, Nonsense
- Ependymoglial Cells/metabolism
- Intellectual Disability*
- Mice
- Phenotype
- Repressor Proteins/genetics
- TOR Serine-Threonine Kinases/genetics
- Zebrafish*/genetics
- Zebrafish*/metabolism
- PubMed
- 36804358 Full text @ Gene
Citation
Castro, V.L., Paz, D., Virrueta, V., Estevao, I.L., Grajeda, B.I., Ellis, C.C., Quintana, A.M. (2023) Missense and nonsense mutations of the zebrafish hcfc1a gene result in contrasting mTor and radial glial phenotypes. Gene. 864:147290.
Abstract
Mutations in the HCFC1 transcriptional co-factor protein are the cause of cblX syndrome and X-linked intellectual disability (XLID). cblX is the more severe disorder associated with intractable epilepsy, abnormal cobalamin metabolism, facial dysmorphia, cortical gyral malformations, and intellectual disability. In vitro, murine Hcfc1 regulates neural precursor (NPCs) proliferation and number, which has been validated in zebrafish. However, conditional deletion of mouse Hcfc1 in Nkx2.1+ cells increased cell death, reduced Gfap expression, and reduced numbers of GABAergic neurons. Thus, the role of this gene in brain development is not completely understood. Recently, knock-in of both a cblX (HCFC1) and cblX-like (THAP11) allele were created in mice. Knock-in of the cblX-like allele was associated with increased expression of proteins required for ribosome biogenesis. However, the brain phenotypes were not comprehensively studied due to sub-viability. Therefore, a mechanism underlying increased ribosome biogenesis was not described. We used a missense, a nonsense, and two conditional zebrafish alleles to further elucidate this mechanism during brain development. We observed contrasting phenotypes at the level of Akt/mTor activation, the number of radial glial cells, and the expression of two downstream target genes of HCFC1, asxl1 and ywhab. Despite these divergent phenotypes, each allele studied demonstrates with a high degree of face validity when compared to the phenotypes reported in the literature. Collectively, these data suggest that individual mutations in the HCFC1 protein result in differential mTOR activity which may be associated with contrasting cellular phenotypes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping