PUBLICATION

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

Authors

Quintana, A.M., Hernandez, J.A., Gonzalez, C.G.

ID

ZDB-PUB-170708-5

Date

2017

Source

PLoS One 12: e0180856 (Journal)

Registered Authors

Quintana, Anita

Keywords

Cholesterol, Embryos, Isoprenoids, Cartilage, Face, Zebrafish, Fertilization, Larvae

MeSH Terms

Cholesterol/biosynthesis*
Hedgehog Proteins/genetics*
Hedgehog Proteins/metabolism
Cell Differentiation/drug effects
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism
Hydroxymethylglutaryl-CoA Synthase/genetics*
Hydroxymethylglutaryl-CoA Synthase/metabolism
Neural Crest/drug effects
Neural Crest/metabolism
Neural Crest/pathology
Anticholesteremic Agents/pharmacology
Terpenes/antagonists & inhibitors
Terpenes/metabolism*
Piperidines/pharmacology
Animals
Zebrafish
Chondrocytes/drug effects
Chondrocytes/metabolism
Chondrocytes/pathology
Humans
Signal Transduction
Atorvastatin/pharmacology
Gene Expression Regulation, Developmental
Benzophenones/pharmacology
Body Patterning/drug effects
Body Patterning/genetics
Enzyme Inhibitors/pharmacology
Pyridines/pharmacology
Hydroxymethylglutaryl CoA Reductases/genetics*
Hydroxymethylglutaryl CoA Reductases/metabolism
Craniofacial Abnormalities/genetics*
Craniofacial Abnormalities/metabolism
Craniofacial Abnormalities/pathology
Zinc Finger Protein GLI1/genetics*
Zinc Finger Protein GLI1/metabolism
Embryo, Nonmammalian

(all 37)

PubMed

28686747 Full text @ PLoS One

Abstract

There are 8 different human syndromes caused by mutations in the cholesterol synthesis pathway. A subset of these disorders such as Smith-Lemli-Opitz disorder, are associated with facial dysmorphia. However, the molecular and cellular mechanisms underlying such facial deficits are not fully understood, primarily because of the diverse functions associated with the cholesterol synthesis pathway. Recent evidence has demonstrated that mutation of the zebrafish ortholog of HMGCR results in orofacial clefts. Here we sought to expand upon these data, by deciphering the cholesterol dependent functions of the cholesterol synthesis pathway from the cholesterol independent functions. Moreover, we utilized loss of function analysis and pharmacological inhibition to determine the extent of sonic hedgehog (Shh) signaling in animals with aberrant cholesterol and/or isoprenoid synthesis. Our analysis confirmed that mutation of hmgcs1, which encodes the first enzyme in the cholesterol synthesis pathway, results in craniofacial abnormalities via defects in cranial neural crest cell differentiation. Furthermore targeted pharmacological inhibition of the cholesterol synthesis pathway revealed a novel function for isoprenoid synthesis during vertebrate craniofacial development. Mutation of hmgcs1 had no effect on Shh signaling at 2 and 3 days post fertilization (dpf), but did result in a decrease in the expression of gli1, a known Shh target gene, at 4 dpf, after morphological deficits in craniofacial development and chondrocyte differentiation were observed in hmgcs1 mutants. These data raise the possibility that deficiencies in cholesterol modulate chondrocyte differentiation by a combination of Shh independent and Shh dependent mechanisms. Moreover, our results describe a novel function for isoprenoids in facial development and collectively suggest that cholesterol regulates craniofacial development through versatile mechanisms.

Genes / Markers

Figures

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Expression

Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
AB	standard conditions	Protruding-mouth		brain ventral region	ISH	Fig. 4
AB	chemical treatment by environment: lonafarnib	Protruding-mouth		brain ventral region	ISH	Fig. 4
AB	standard conditions	Protruding-mouth		brain ventral region	ISH	Fig. 3
AB	standard conditions	Protruding-mouth		oral ectoderm	ISH	Fig. 4
AB	chemical treatment by environment: lonafarnib	Protruding-mouth		oral ectoderm	ISH	Fig. 4
AB	standard conditions	Protruding-mouth		oral ectoderm	ISH	Fig. 3
AB	standard conditions	Protruding-mouth		pharyngeal pouch	ISH	Fig. 4
AB	standard conditions	Protruding-mouth		pharyngeal pouch	ISH	Fig. 3
AB	chemical treatment by environment: lonafarnib	Protruding-mouth	Not Detected	pharyngeal pouch	ISH	Fig. 4
AB	chemical treatment by environment: Ro 48-8071	Protruding-mouth		pharyngeal pouch	ISH	Fig. 4

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: atorvastatin	Day 4	basihyal cartilage absent, abnormal	Table 1
AB	chemical treatment by environment: atorvastatin	Day 4	ceratobranchial cartilage malformed, abnormal	Table 1
AB	chemical treatment by environment: lonafarnib	Protruding-mouth	pharyngeal pouch col2a1a expression absent, abnormal	Fig. 4
AB	chemical treatment by environment: lonafarnib	Day 4	basihyal cartilage absent, abnormal	Fig. 4
AB	chemical treatment by environment: lonafarnib	Day 4	ceratobranchial cartilage malformed, abnormal	Fig. 4
AB	chemical treatment by environment: lonafarnib	Day 4	embryonic viscerocranium morphogenesis disrupted, abnormal	Fig. 4
AB	chemical treatment by environment: lonafarnib	Day 4	Meckel's cartilage truncated, abnormal	Fig. 4
AB	chemical treatment by environment: Ro 48-8071	Protruding-mouth	pharyngeal pouch col2a1a expression decreased amount, abnormal	Fig. 4
AB	chemical treatment by environment: Ro 48-8071	Day 4	ceratobranchial cartilage malformed, abnormal	Fig. 4
AB	chemical treatment by environment: Ro 48-8071	Day 4	embryonic viscerocranium morphogenesis disrupted, abnormal	Fig. 4

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
co26Tg	Tg(sox10:TagRFP)	Transgenic Insertion
vu57		Point Mutation	hmgcs1
vu234Tg	Tg(sox10:mRFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
AB
co26Tg
hmgcs1^vu57/vu57
hmgcs1^vu57/vu57; co26Tg
hmgcs1^vu57/vu57; vu234Tg
vu234Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed2	EFG	DsRed2
mRFP	EFG	mRFP
TagRFP	EFG	TagRFP

Mapping

Quintana et al., 2017 ZDB-PUB-170708-5 PMID:28686747

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

Quintana et al., 2017

ZDB-PUB-170708-5
PMID:28686747