Chemokine signaling links cell-cycle progression and cilia formation for left-right symmetry breaking
- Liu, J., Zhu, C., Ning, G., Yang, L., Cao, Y., Huang, S., Wang, Q.
- PLoS Biology 17: e3000203 (Journal)
- Registered Authors
- Huang, Sizhou, Wang, Qiang
- MeSH Terms
- Body Patterning/genetics
- Cell Cycle/physiology
- Cell Division
- Cell Proliferation
- Embryo, Nonmammalian/metabolism
- Forkhead Transcription Factors/metabolism
- G1 Phase Cell Cycle Checkpoints/physiology
- Gene Expression Regulation, Developmental/genetics
- Left-Right Determination Factors/metabolism*
- Receptors, CXCR4/metabolism*
- Receptors, CXCR4/physiology
- Signal Transduction
- Zebrafish Proteins/metabolism*
- Zebrafish Proteins/physiology
- 31430272 Full text @ PLoS Biol.
Liu, J., Zhu, C., Ning, G., Yang, L., Cao, Y., Huang, S., Wang, Q. (2019) Chemokine signaling links cell-cycle progression and cilia formation for left-right symmetry breaking. PLoS Biology. 17:e3000203.
Zebrafish dorsal forerunner cells (DFCs) undergo vigorous proliferation during epiboly and then exit the cell cycle to generate Kupffer's vesicle (KV), a ciliated organ necessary for establishing left-right (L-R) asymmetry. DFC proliferation defects are often accompanied by impaired cilia elongation in KV, but the functional and molecular interaction between cell-cycle progression and cilia formation remains unknown. Here, we show that chemokine receptor Cxcr4a is required for L-R laterality by controlling DFC proliferation and KV ciliogenesis. Functional analysis revealed that Cxcr4a accelerates G1/S transition in DFCs and stabilizes forkhead box j1a (Foxj1a), a master regulator of motile cilia, by stimulating Cyclin D1 expression through extracellular regulated MAP kinase (ERK) 1/2 signaling. Mechanistically, Cyclin D1-cyclin-dependent kinase (CDK) 4/6 drives G1/S transition during DFC proliferation and phosphorylates Foxj1a, thereby disrupting its association with proteasome 26S subunit, non-ATPase 4b (Psmd4b), a 19S regulatory subunit. This prevents the ubiquitin (Ub)-independent proteasomal degradation of Foxj1a. Our study uncovers a role for Cxcr4 signaling in L-R patterning and provides fundamental insights into the molecular linkage between cell-cycle progression and ciliogenesis.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes