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Pair-wise regulation of convergence and extension cell movements by four phosphatases via RhoA
Mark van Eekelen1, Vincent Runtuwene, Wouter Masselink
1Hubrecht Institute and University Medical Center Utrecht, Utrecht, The Netherlands.
Abstract:
Various signaling pathways regulate shaping of the main body axis during early vertebrate development. Here, we focused on the role of protein-tyrosine phosphatase signaling in convergence and extension cell movements. We identified Ptpn20 as a structural paralogue of PTP-BL and both phosphatases were required for normal gastrulation cell movements. Interestingly, knockdowns of PTP-BL and Ptpn20 evoked similar developmental defects as knockdown of RPTPα and PTPε. Co-knockdown of RPTPα and PTP-BL, but not Ptpn20, had synergistic effects and conversely, PTPε and Ptpn20, but not PTP-BL, cooperated, demonstrating the specificity of our approach. RPTPα and PTPε knockdowns were rescued by constitutively active RhoA, whereas PTP-BL and Ptpn20 knockdowns were rescued by dominant negative RhoA. Consistently, RPTPα and PTP-BL had opposite effects on RhoA activation, both in a PTP-dependent manner. Downstream of the PTPs, we identified NGEF and Arhgap29, regulating RhoA activation and inactivation, respectively, in convergence and extension cell movements. We propose a model in which two phosphatases activate RhoA and two phosphatases inhibit RhoA, resulting in proper cell polarization and normal convergence and extension cell movements.
Insights
Protein-tyrosine phosphatases regulate vertebrate body axis formation. Two phosphatases activate RhoA, while two inhibit it, ensuring proper cell movements during gastrulation.
Area of Science:
- Developmental Biology
- Cell Signaling
- Molecular Genetics
Background:
- Vertebrate body axis formation relies on complex signaling pathways.
- Protein-tyrosine phosphatases (PTPs) are key regulators of cellular processes.
- Their specific roles in early development, particularly cell movements, require further elucidation.
Purpose of the Study:
- To investigate the function of PTP-BL and Ptpn20 in vertebrate gastrulation.
- To determine the involvement of PTP signaling in convergence and extension cell movements.
- To elucidate the regulatory mechanisms of RhoA signaling by PTPs during development.
Main Methods:
- Gene knockdown studies in vertebrate models.
- Analysis of developmental defects and cell movement patterns.
- Investigation of RhoA activation and downstream effectors.
Main Results:
- Ptpn20 is a paralogue of PTP-BL; both are essential for normal gastrulation.
- Specific PTPs (RPTPα, PTPε) activate RhoA, while others (PTP-BL, Ptpn20) inhibit it.
- NGEF and Arhgap29 were identified as downstream regulators of RhoA in these processes.
Conclusions:
- A model is proposed where opposing PTP-RhoA pathways control cell polarization.
- This balance is critical for normal convergence and extension cell movements.
- Understanding these PTP networks offers insights into developmental mechanisms.
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