PUBLICATION

ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2

Authors

Park, S.O., Lee, Y.J., Seki, T., Hong, K.H., Fliess, N., Jiang, Z., Park, A., Wu, X., Kaartinen, V., Roman, B.L., and Oh, S.P.

ID

ZDB-PUB-110712-1

Date

2008

Source

Blood 111(2): 633-642 (Journal)

Registered Authors

Roman, Beth

Keywords

none

MeSH Terms

Cell Line
Mice, Knockout
Protein Serine-Threonine Kinases/genetics
Protein Serine-Threonine Kinases/metabolism*
Receptors, Transforming Growth Factor beta/genetics
Receptors, Transforming Growth Factor beta/metabolism*
Zebrafish Proteins
Neovascularization, Pathologic/genetics
Neovascularization, Pathologic/metabolism*
Neovascularization, Pathologic/pathology
Ligands
Signal Transduction*/genetics
Activin Receptors, Type I/genetics
Activin Receptors, Type I/metabolism*
Telangiectasia, Hereditary Hemorrhagic/genetics
Telangiectasia, Hereditary Hemorrhagic/metabolism*
Telangiectasia, Hereditary Hemorrhagic/pathology
Endothelium, Vascular/metabolism
Endothelium, Vascular/pathology
Mice
Zebrafish/genetics
Zebrafish/metabolism
Transforming Growth Factor beta1/genetics
Transforming Growth Factor beta1/metabolism
Animals

(all 25)

PubMed

17911384 Full text @ Blood

Abstract

ALK1 belongs to the type I receptor family for transforming growth factor-β family ligands. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia type 2 (HHT2), a multisystemic vascular disorder. Based largely on in vitro studies, TGF-β1 has been considered as the most likely ALK1 ligand related to HHT, yet the identity of the physiologic ALK1 ligand remains controversial. In cultured endothelial cells, ALK1 and another TGF-β type I receptor, ALK5, regulate angiogenesis by controlling TGF-β signal transduction, and ALK5 is required for ALK1 signaling. However, the extent to which such interactions between these 2 receptors play a role in pathogenesis of HHT is unknown. We directly addressed these issues in vivo by comparing the phenotypes of mice in which the Alk1, Alk5, or Tgfbr2 gene was conditionally deleted in restricted vascular endothelia using a novel endothelial Cre transgenic line. Alk1-conditional deletion resulted in severe vascular malformations mimicking all pathologic features of HHT. Yet Alk5- or Tgfbr2-conditional deletion in mice, or Alk5 inhibition in zebrafish, did not affect vessel morphogenesis. These data indicate that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to the pathogenesis of HHT and suggest that HHT might not be a TGF-β subfamily disease.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
cdh5	WT	standard conditions	Prim-5	vasculature	ISH	Fig. 8
cdh5	WT	standard conditions	Long-pec	vasculature	ISH	Fig. 8
tgfbr1a	WT	standard conditions	Prim-5	brain	ISH	Fig. 8
tgfbr1a	WT	standard conditions	Long-pec	brain	ISH	Fig. 8
tgfbr1a	WT	standard conditions	Prim-5	endoderm	ISH	Fig. 8
tgfbr1a	WT	standard conditions	Long-pec	endoderm	ISH	Fig. 8
tgfbr1a	WT	standard conditions	Prim-5	eye	ISH	Fig. 8
tgfbr1a	WT	standard conditions	Long-pec	eye	ISH	Fig. 8
tgfbr1a	WT	standard conditions	Long-pec	pharyngeal arch	ISH	Fig. 8
tgfbr1a	WT	standard conditions	Prim-5	pharyngeal arch	ISH	Fig. 8

1 - 10 of 25

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
acvrl1^y6/y6; la116Tg	control	Long-pec	basal communicating artery increased size, abnormal	Fig. 8
acvrl1^y6/y6; la116Tg	control	Long-pec	posterior communicating artery increased size, abnormal	Fig. 8
acvrl1^y6/y6; la116Tg	control	Long-pec	primordial hindbrain channel increased size, abnormal	Fig. 8

1 - 3 of 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
la116Tg	Tg(kdrl:GFP)	Transgenic Insertion
y6		Point Mutation	acvrl1

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
acvrl1^y6/y6; la116Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Entity Type	Entity Symbol	Location
GENE	tgfbr1a	Chr: 2 Details
GENE	tgfbr1b	Chr: 24 Details

Park et al., 2008 ZDB-PUB-110712-1 PMID:17911384

ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2

Park et al., 2008

ZDB-PUB-110712-1
PMID:17911384