Alkylglycerol monooxygenase, a heterotaxy candidate gene, regulates left-right patterning via Wnt signaling

被引:4
作者
Duncan, Anna R. [1 ]
Gonzalez, Delfina P. [1 ]
del Viso, Florencia [1 ]
Robson, Andrew [1 ]
Khokha, Mustafa K. [1 ]
Griffin, John N. [1 ,2 ]
机构
[1] Yale Univ, Sch Med, Dept Pediat & Genet, Pediat Genom Discovery Program, 333 Cedar St, New Haven, CT 06510 USA
[2] Univ East Anglia, Sch Biol Sci, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England
关键词
Alkylglycerol monooxygenase; Ether lipids; AGMO; TMEM195; Heterotaxy; Wnt; Xenopus; Congenital heart disease; CONGENITAL HEART-DISEASE; LEFT-RIGHT ASYMMETRY; LEFT-RIGHT AXIS; BETA-CATENIN; TRANSCRIPTION FACTOR; SPEMANNS ORGANIZER; FOXJ1; EXPRESSION; XENOPUS; MOUSE; NODE;
D O I
10.1016/j.ydbio.2019.07.019
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Congenital heart disease (CHD) is a major cause of morbidity in the pediatric population yet its genetic and molecular causes remain poorly defined. Previously, we identified AGMO as a candidate heterotaxy disease gene, a disorder of left-right (LR) patterning that can have a profound effect on cardiac function. AGMO is the only known alkylglycerol monooxygenase, an orphan tetrahydrobiopterin dependent enzyme that cleaves the ether linkage in alkylglycerols. However, whether AGMO plays a role in LR patterning was unexplored. Here we reveal that Agmo is required for correct development of the embryonic LR axis in Xenopus embryos recapitulating the patient's heterotaxy phenotype. Mechanistically, we demonstrate that Agmo is a regulator of canonical Wnt signaling, required during gastrulation for normal formation of the left right organizer. Mutational analysis demonstrates that this function is dependent on Agmo's alkylglycerol monooxygenase activity. Together, our findings identify Agmo as a regulator of canonical Wnt signaling, demonstrate a role for Agmo in embryonic axis formation, and provide insight into the poorly understood developmental requirements for ether lipid cleavage.
引用
收藏
页码:1 / 7
页数:7
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