MondoA regulates gene expression in cholesterol biosynthesis-associated pathways required for zebrafish epiboly.
carbohydrate response element
cholesterol
developmental biology
epiboly
genetics
genomics
metabolism
microtubule
pregnenolone
zebrafish
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
24 09 2020
24 09 2020
Historique:
received:
19
03
2020
accepted:
18
08
2020
entrez:
24
9
2020
pubmed:
25
9
2020
medline:
16
3
2021
Statut:
epublish
Résumé
The glucose-sensing Mondo pathway regulates expression of metabolic genes in mammals. Here, we characterized its function in the zebrafish and revealed an unexpected role of this pathway in vertebrate embryonic development. We showed that knockdown of In most animals, a protein called MondoA closely monitors the amount of glucose in the body, as this type of sugar is the fuel required for many life processes. Glucose levels also act as a proxy for the availability of other important nutrients. Once MondoA has detected glucose molecules, it turns genetic programmes on and off depending on the needs of the cell. So far, these mechanisms have mainly been studied in adult cells. However, recent studies have shown that proteins that monitor nutrient availability, and their associated pathways, can control early development. MondoA had not been studied in this context before, so Weger et al. decided to investigate its role in embryonic development. The experiments used embryos from zebrafish, a small freshwater fish whose early development is easily monitored and manipulated in the laboratory. Inhibiting production of the MondoA protein in zebrafish embryos prevented them from maturing any further, stopping their development at an early key stage. This block was caused by defects in microtubules, the tubular molecules that act like a microscopic skeleton to provide structural support for cells and guide transport of cell components. In addition, the pathway involved in the production of cholesterol and cholesterol-based hormones was far less active in embryos lacking MondoA. Treating MondoA-deficient embryos with one of these hormones corrected the microtubule defects and let the embryos progress to more advanced stages of development. These results reveal that, during development, the glucose sensor MondoA also controls pathways involved in the creation of cholesterol and associated hormones. These new insights into the metabolic regulation of development could help to understand certain human conditions; for example, certain patients with defective cholesterol pathway genes also show developmental perturbations. In addition, the work highlights a biological link between cholesterol production and cellular responses to glucose, which Weger et al. hope could one day help to identify new cholesterol-lowering drugs.
Autres résumés
Type: plain-language-summary
(eng)
In most animals, a protein called MondoA closely monitors the amount of glucose in the body, as this type of sugar is the fuel required for many life processes. Glucose levels also act as a proxy for the availability of other important nutrients. Once MondoA has detected glucose molecules, it turns genetic programmes on and off depending on the needs of the cell. So far, these mechanisms have mainly been studied in adult cells. However, recent studies have shown that proteins that monitor nutrient availability, and their associated pathways, can control early development. MondoA had not been studied in this context before, so Weger et al. decided to investigate its role in embryonic development. The experiments used embryos from zebrafish, a small freshwater fish whose early development is easily monitored and manipulated in the laboratory. Inhibiting production of the MondoA protein in zebrafish embryos prevented them from maturing any further, stopping their development at an early key stage. This block was caused by defects in microtubules, the tubular molecules that act like a microscopic skeleton to provide structural support for cells and guide transport of cell components. In addition, the pathway involved in the production of cholesterol and cholesterol-based hormones was far less active in embryos lacking MondoA. Treating MondoA-deficient embryos with one of these hormones corrected the microtubule defects and let the embryos progress to more advanced stages of development. These results reveal that, during development, the glucose sensor MondoA also controls pathways involved in the creation of cholesterol and associated hormones. These new insights into the metabolic regulation of development could help to understand certain human conditions; for example, certain patients with defective cholesterol pathway genes also show developmental perturbations. In addition, the work highlights a biological link between cholesterol production and cellular responses to glucose, which Weger et al. hope could one day help to identify new cholesterol-lowering drugs.
Identifiants
pubmed: 32969791
doi: 10.7554/eLife.57068
pii: 57068
pmc: PMC7515633
doi:
pii:
Substances chimiques
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
0
Zebrafish Proteins
0
Cholesterol
97C5T2UQ7J
Banques de données
GEO
['GSE144350']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Marie Curie Intra-European Fellowship
ID : PIEF-GA-2013-625827
Pays : International
Organisme : Helmholtz-Gemeinschaft
ID : BioInterfaces in Technology and Medicine (BIFTM)
Pays : International
Organisme : Helmholtz-Gemeinschaft
ID : Science and Technology of Nanostructures (STN)
Pays : International
Informations de copyright
© 2020, Weger et al.
Déclaration de conflit d'intérêts
MW, AS, MT, JS, AK, JM, NK, US, GN, RM, TD No competing interests declared, BW BDW was an employee of Nestlé Health Sciences SA. CG CG was an employee of Nestlé Health Sciences SA. AP AP is an employee of Nestlé Health Sciences SA. FG FG was an employee of Nestlé Health Sciences SA. PG PG is an employee of Nestlé Health Sciences SA.
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