PUBLICATION

Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating MMACHC expression

Authors

Quintana, A.M., Geiger, E.A., Achilly, N., Rosenblatt, D.S., Maclean, K.N., Stabler, S.P., Artinger, K.B., Appel, B., Shaikh, T.H.

ID

ZDB-PUB-141005-7

Date

2014

Source

Developmental Biology 396(1): 94-106 (Journal)

Registered Authors

Appel, Bruce, Artinger, Kristin Bruk

Keywords

Cobalamin, Craniofacial defects, Facial dysmorphia, HCFC1, MMACHC

MeSH Terms

Humans
Carrier Proteins/genetics
Carrier Proteins/physiology*
Gene Knockdown Techniques
Cell Differentiation
Zebrafish Proteins/genetics
Zebrafish Proteins/physiology*
Vitamin B 12/metabolism
Zebrafish/genetics
Neural Crest/cytology
Neural Crest/physiology
Stem Cells/cytology
Mutation
Body Patterning/genetics
Green Fluorescent Proteins/metabolism
Cell Movement
Mice, Transgenic
Animals
Branchial Region/physiology
Craniofacial Abnormalities/genetics
Chondrocytes/cytology
Gene Expression Regulation, Developmental*
Phenotype
Host Cell Factor C1/genetics
Host Cell Factor C1/physiology*

(all 25)

PubMed

25281006 Full text @ Dev. Biol.

Abstract

Mutations in HCFC1 (MIM300019), have been recently associated with cblX (MIM309541), an X-linked, recessive disorder characterized by multiple congenital anomalies including craniofacial abnormalities. HCFC1 is a transcriptional co-regulator that modulates the expression of numerous downstream target genes including MMACHC, but it is not clear how these HCFC1 targets play a role in the clinical manifestations of cblX. To begin to elucidate the mechanism by which HCFC1 modulates disease phenotypes, we have carried out loss of function analyses in the developing zebrafish. Of the two HCFC1 orthologs in zebrafish, hcfc1a and hcfc1b, the loss of hcfc1b specifically results in defects in craniofacial development. Subsequent analysis revealed that hcfc1b regulates cranial neural crest cell differentiation and proliferation within the posterior pharyngeal arches. Further, the hcfc1b-mediated craniofacial abnormalities were rescued by expression of human MMACHC, a downstream target of HCFC1 that is aberrantly expressed in cblX. Furthermore, we tested distinct human HCFC1 mutations for their role in craniofacial development and demonstrated variable effects on MMACHC expression in humans and craniofacial development in zebrafish. Notably, several individuals with mutations in either HCFC1 or MMACHC have been reported to have mild to moderate facial dysmorphia. Thus, our data demonstrates that HCFC1 plays a role in craniofacial development, which is in part mediated through the regulation of MMACHC expression.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
col2a1b	WT	standard conditions	Protruding-mouth		splanchnocranium chondrocyte	ISH	Fig. 4
col2a1b	WT + MO1-hcfc1b + MO4-tp53	standard conditions	Protruding-mouth	Not Detected	ceratobranchial cartilage	ISH	Fig. 4
col2a1b	WT + MO1-hcfc1b + MO4-tp53	standard conditions	Protruding-mouth		splanchnocranium chondrocyte	ISH	Fig. 4
dlx2a	WT	standard conditions	Prim-5		forebrain	ISH	Fig. 3
dlx2a	WT	standard conditions	Prim-5		pharyngeal arch anatomical region	ISH	Fig. 3
dlx2a	WT + MO1-hcfc1b + MO4-tp53	standard conditions	Prim-5		forebrain	ISH	Fig. 3
dlx2a	WT + MO1-hcfc1b + MO4-tp53	standard conditions	Prim-5		pharyngeal arch anatomical region	ISH	Fig. 3
EGFP	ba2Tg	standard conditions	Protruding-mouth to Day 5		pharyngeal arch cranial neural crest cell	IHC	Fig. 5
EGFP	ba2Tg + MO1-hcfc1b + MO4-tp53	standard conditions	Protruding-mouth to Day 5		pharyngeal arch cranial neural crest cell	IHC	Fig. 5
EGFP	i106Tg	standard conditions	Prim-5		pharyngeal arch anatomical region	IFL	Fig. 3

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Protruding-mouth	ceratobranchial cartilage absent, abnormal	Fig. 4
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 4	ceratobranchial cartilage absent, abnormal	Fig. 7
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 4	ceratohyal cartilage malformed, abnormal	Fig. 7
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 4	Meckel's cartilage malformed, abnormal	Fig. 7
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 4	splanchnocranium malformed, abnormal	Fig. 7
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 5	ceratobranchial cartilage absent, abnormal	Fig. 2
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 5	ceratobranchial cartilage absent, abnormal	Fig. 9
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 5	ceratohyal cartilage inverted, abnormal	Fig. 2
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 5	ceratohyal cartilage malformed, abnormal	Fig. 2
WT + MO1-hcfc1b + MO4-tp53	standard conditions	Day 5	ceratohyal cartilage malformed, abnormal	Fig. 9

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Mutations / Transgenics

Allele	Construct	Type
ba2Tg	Tg(-4.9sox10:EGFP)	Transgenic Insertion
i106Tg	TgPAC(prdm1a:EGFP)	Transgenic Insertion
vu234Tg	Tg(sox10:mRFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
hcfc1a	MO1-hcfc1a	MRPHLNO
hcfc1b	MO1-hcfc1b	MRPHLNO
mmachc	MO1-mmachc	MRPHLNO
tp53	MO4-tp53	MRPHLNO

Fish

Fish
ba2Tg
ba2Tg + MO1-hcfc1b + MO4-tp53
i106Tg
i106Tg + MO1-hcfc1b + MO4-tp53
vu234Tg
vu234Tg + MO1-hcfc1b + MO4-tp53
WT
WT + MO1-hcfc1b + MO4-tp53
WT + MO1-mmachc + MO4-tp53

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
mRFP	EFG	mRFP
RFP	EFG	RFP

Mapping

Quintana et al., 2014 ZDB-PUB-141005-7 PMID:25281006

Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating MMACHC expression

Quintana et al., 2014

ZDB-PUB-141005-7
PMID:25281006