Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development

Quintana, Anita M.; Hernández, José Ángel; Gonzalez, Cesar G.

doi:10.1371/journal.pone.0180856

Cited by 29 publications

(81 citation statements)

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“…All embryos were maintained in embryo medium at 28 • C and all experiments were performed according to protocol 811689-5 approved by The University of Texas El Paso Institutional Animal Care and Use Committee (IACUC). Genotyping was performed as previously described 35 .…”

Section: Zebrafish Carementioning

confidence: 99%

“…2017 35 . Drugs were diluted in embryo medium to make working solutions at the following concentrations: 2.0 uM atorvastatin [34][35][36] , 8 uM lonafarnib 34,37 , and 1.5uM Ro 48 8071. Final concentration of DMSO was less than 0.01 % in all samples and vehicle control treatment.…”

Section: Drug Treatments and Morpholino Injectionmentioning

confidence: 99%

“…Hemoglobin was measured with the Hemoglobin Assay Kit (Sigma-Aldrich, St. Louis, MO) according to manufacturer's protocol. For analysis of the Vu57 allele, larvae were separated via distinct phenotypic hallmarks described previously 34,35 . The control contained both homozygous wildtype and heterozygous individuals harboring the Vu57 allele.…”

Section: Hemoglobin Quantificationmentioning

confidence: 99%

“…The VU57 allele abrogates cholesterol synthesis causing a multiple congenital anomaly syndrome characterized by defects in myelination, myelin gene expression, cardiac edema, pigment defects and craniofacial abnormalities 34,35 . We first detected the number of We next quantified the decrease in circulating RBCs in homozygous mutants and their siblings.…”

Section: Mutations In Hmgcs1 Disrupt Rbc Developmentmentioning

confidence: 99%

“…Mutation of hmgcs1 disrupts the first enzyme of the CSP 34 effectively interfering with the production of both cholesterol and isoprenoids. Recent evidence suggests that each of these two lipids can regulate the same biological process, however by independent molecular and cellular mechanisms 34,35,37 . We hypothesized that the defects observed in mutant larvae are cholesterol dependent.…”

Section: Cholesterol and Isoprenoids Regulate Rbc Developmentmentioning

confidence: 99%

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Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

Hernández

Castro

Reyes-Nava

et al. 2018

Preprint

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word count: 187 Number of figures and tables: 5 Number of references: 72 Key Points 1. The products of the cholesterol synthesis pathway regulate red blood cell development during primitive erythropoiesis. 2. Isoprenoids regulate erythropoiesis by modulating the expression of the GATA1 transcription factor. AbstractErythropoiesis is the process by which new red blood cells (RBCs) are formed and defects in this process can lead to anemia or thalassemia. The GATA1 transcription factor is an established mediator of RBC development. However, the upstream mechanisms that regulate the expression of GATA1 are not completely characterized. Cholesterol is one potential upstream mediator of GATA1 expression because previously published studies suggest that defects in cholesterol synthesis disrupt RBC differentiation. Here we characterize RBC development in a zebrafish harboring a single missense mutation in the hmgcs1 gene (Vu57 allele). hmgcs1 encodes the first enzyme in the cholesterol synthesis pathway and mutation of hmgcs1 inhibits cholesterol synthesis. We analyzed the number of RBCs in hmgcs1 mutants and their wildtype siblings. Mutation of hmgcs1 resulted in a decrease in the number of mature RBCs, which coincides with reduced gata1a expression. We combined these experiments with pharmacological inhibition and confirmed that cholesterol and isoprenoid synthesis are essential for RBC differentiation, but that gata1a expression is isoprenoid dependent. Collectively, our results reveal two novel upstream regulators of RBC development and suggest that appropriate cholesterol homeostasis is critical for primitive erythropoiesis.

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Section: Zebrafish Carementioning

confidence: 99%

Section: Drug Treatments and Morpholino Injectionmentioning

confidence: 99%

Section: Hemoglobin Quantificationmentioning

confidence: 99%

Section: Mutations In Hmgcs1 Disrupt Rbc Developmentmentioning

confidence: 99%

Section: Cholesterol and Isoprenoids Regulate Rbc Developmentmentioning

confidence: 99%

See 3 more Smart Citations

Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

Hernández

Castro

Reyes-Nava

et al. 2018

Preprint

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Differentially sensitive neuronal subpopulations in the central nervous system and the formation of hindbrain heterotopias in ethanol‐exposed zebrafish

Buckley

Sidik

Kar

et al. 2019

Birth Defects Research

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Background A cardinal feature of prenatal ethanol exposure is CNS damage, resulting in a continuum of neurological and behavioral impairments that are described by the term Fetal Alcohol Spectrum Disorders (FASD). FASDs are variable and depend on several factors, including the amount, timing and duration of prenatal ethanol exposure. To enhance interventions for CNS dysfunction, it is necessary to identify ethanol-sensitive neuronal populations and expand the understanding of factors that modify ethanol teratogenesis. Methods: To investigate the susceptibility of different neuronal subtypes, we exposed transgenic zebrafish (Danio rerio) to several ethanol concentrations (0.25%, 0.5%, 1.0%, 1.5% or 2.0%), at different hours post fertilization (hpf) (0 hpf, 6 hpf or 24 hpf), for various durations (0–24hpf, 0–48hpf, 4–24hpf, 6–24hpf, 6–48hpf or 24–48hpf). Following exposure, embryo survival rates were determined, and CNS neurogenesis, differentiation and patterning was assessed. Results: Embryo survival rates decrease as ethanol concentrations increase and drastically decline when exposed from 0–24hpf compared to 4–24hpf. Abnormal tangential migration of facial motor neurons is observed in isl1:gfp embryos exposed to ethanol concentrations as low as 0.25%, and the formation of IVth ventricle heterotopias are revealed by embryos exposed to ≥1.0% ethanol. Whereas, expression of olig2:dsred and ptf1a:gfp in the cerebellum and spinal cord are largely unaffected. While levels of etv4 mRNA are overtly resistant to ethanol, we observe significant reductions in ptch2 mRNA levels. Conclusions: These data show differentially sensitive CNS neuron subpopulations with susceptibility to low levels of ethanol. In addition, these data reveal the formation of ethanol-induced hindbrain heterotopias.

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Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

Castro

Reyes-Nava

Sanchez

et al. 2020

Genesis

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Inborn errors of cholesterol metabolism occur as a result of mutations in the cholesterol synthesis pathway (CSP). Although mutations in the CSP cause a multiple congenital anomaly syndrome, craniofacial abnormalities are a hallmark phenotype associated with these disorders. Previous studies have established that mutation of the zebrafish hmgcs1 gene (Vu57 allele), which encodes the first enzyme in the CSP, causes defects in craniofacial development and abnormal neural crest cell (NCC) differentiation. However, the molecular mechanisms by which the products of the CSP disrupt NCC differentiation are not completely known. Cholesterol is known to regulate the activity of WNT signaling, an established regulator of NCC differentiation. We hypothesized that defects in cholesterol synthesis are associated with reduced WNT signaling, consequently resulting in abnormal craniofacial development. To test our hypothesis we performed a combination of pharmaceutical inhibition, gene expression assays, and targeted rescue experiments to understand the function of the CSP and WNT signaling during craniofacial development. We demonstrate reduced expression of four canonical WNT downstream target genes in homozygous carriers of the Vu57 allele and reduced axin2 expression, a known WNT target gene, in larvae treated with Ro-48-8071, an inhibitor of cholesterol synthesis. Moreover, activation of WNT signaling via treatment with WNT agonist I completely restored the craniofacial defects present in a subset of animals carrying the Vu57 allele. Collectively, these data suggest interplay between the CSP and WNT signaling during craniofacial development.

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Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development

Cited by 29 publications

References 50 publications

Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

Differentially sensitive neuronal subpopulations in the central nervous system and the formation of hindbrain heterotopias in ethanol‐exposed zebrafish

Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism

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