期刊
NATURE CELL BIOLOGY
卷 21, 期 6, 页码 721-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0330-5
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资金
- American Heart Association [14POST18340021]
- Leukemia and Lymphoma Society [5431-15, 1657-13]
- National Heart, Lung, and Blood Institute of the US National Institutes of Health (NIH) [K99HL133458]
- UCSD Interdisciplinary Stem Cell Training Program [CIRM TG2-01154]
- American Heart Association Predoctoral Fellowship [16PRE27340012]
- UCSD Stem Cell Program
- CIRM Major Facilities grant [FA1-00607]
- CIRM [RB4-06158]
- NIH/National Heart, Lung, and Blood Institute [R01HL135205]
- NIH/National Institute of General Medical Sciences [R01GM110304]
- Graduate Training in Cellular and Molecular Pharmacology Training Grant [NIH T32 GM007752]
- Harvard Stem Cell Institute
- NIDDK [UH2/3DK107372]
Wnt signalling drives many processes in development, homeostasis and disease; however, the role and mechanism of individual ligand-receptor (Wnt-Frizzled (Fzd)) interactions in specific biological processes remain poorly understood. Wnt9a is specifically required for the amplification of blood progenitor cells during development. Using genetic studies in zebrafish and human embryonic stem cells, paired with in vitro cell biology and biochemistry, we determined that Wnt9a signals specifically through Fzd9b to elicit beta-catenin-dependent Wnt signalling that regulates haematopoietic stem and progenitor cell emergence. We demonstrate that the epidermal growth factor receptor (EGFR) is required as a cofactor for Wnt9a-Fzd9b signalling. EGFR-mediated phosphorylation of one tyrosine residue on the Fzd9b intracellular tail in response to Wnt9a promotes internalization of the Wnt9a-Fzd9b-LRP signalosome and subsequent signal transduction. These findings provide mechanistic insights for specific Wnt-Fzd signals, which will be crucial for specific therapeutic targeting and regenerative medicine.
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