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Missense and nonsense mutations of the zebrafish hcfc1a gene result in contrasting mTor and radial glial phenotypes

Victoria L. Castro, David Paz, Valeria Virrueta, Igor L. Estevao, Brian I. Grajeda, Cameron C. Ellis, View ORCID ProfileAnita M. Quintana
doi: https://doi.org/10.1101/2022.10.21.513292
Victoria L. Castro
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968 USA
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David Paz
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968 USA
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Valeria Virrueta
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968 USA
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Igor L. Estevao
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968 USA
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Brian I. Grajeda
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968 USA
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Cameron C. Ellis
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968 USA
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Anita M. Quintana
Department of Biological Sciences, Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968 USA
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  • ORCID record for Anita M. Quintana
  • For correspondence: Aquintana8@utep.edu
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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, Hcfc1 regulates neural precursor (NPCs) proliferation and number, which has been validated in zebrafish. However, conditional deletion of Hcfc1 in Nkx2.1+ NPCs increased cell death, reduced Gfap expression, and reduced numbers of GABAergic neurons. Thus, the role of HCFC1 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 and 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 is associated with contrasting cellular phenotypes.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • This version has been used to update a change to the title, an updated discussion as per conclusions for the role of asxl1 as a downstream mediator of HCFC1, and to enhance the validity of zebrafish as a model system. The figures remain unchanged and the primary conclusions are equivalent to the original.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 11, 2022.
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Missense and nonsense mutations of the zebrafish hcfc1a gene result in contrasting mTor and radial glial phenotypes
Victoria L. Castro, David Paz, Valeria Virrueta, Igor L. Estevao, Brian I. Grajeda, Cameron C. Ellis, Anita M. Quintana
bioRxiv 2022.10.21.513292; doi: https://doi.org/10.1101/2022.10.21.513292
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Missense and nonsense mutations of the zebrafish hcfc1a gene result in contrasting mTor and radial glial phenotypes
Victoria L. Castro, David Paz, Valeria Virrueta, Igor L. Estevao, Brian I. Grajeda, Cameron C. Ellis, Anita M. Quintana
bioRxiv 2022.10.21.513292; doi: https://doi.org/10.1101/2022.10.21.513292

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