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Updated: Jun 18, 2025
Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
Hippo pathway inactivation through subcellular localization of NF2/merlin in outer cells of mouse embryos
Nanami Goda1, Yui Ito1, Shun Saito1
1Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan.
Abstract:
The Hippo pathway plays a crucial role in cell proliferation and differentiation during tumorigenesis, tissue homeostasis and early embryogenesis. Scaffold proteins from the ezrin-radixin-moesin (ERM) family, including neurofibromin 2 (NF2; Merlin), regulate the Hippo pathway through cell polarity. However, the mechanisms underlying Hippo pathway regulation via cell polarity in establishing outer cells remain unclear. In this study, we generated artificial Nf2 mutants in the N-terminal FERM domain (L64P) and examined Hippo pathway activity by assessing the subcellular localization of YAP1 in early embryos expressing these mutant mRNAs. The L64P-Nf2 mutant inhibited NF2 localization around the cell membrane, resulting in YAP1 cytoplasmic translocation in the polar cells. L64P-Nf2 expression also disrupted the apical centralization of both large tumor suppressor 2 (LATS2) and ezrin in the polar cells. Furthermore, Lats2 mutants in the FERM binding domain (L83K) inhibited YAP1 nuclear translocation. These findings demonstrate that NF2 subcellular localization mediates cell polarity establishment involving ezrin centralization. This study provides previously unreported insights into how the orchestration of the cell-surface components, including NF2, LATS2 and ezrin, modulates the Hippo pathway during cell polarization.
Insights
Neurofibromin 2 (NF2) localization at the cell membrane is vital for Hippo pathway regulation and cell polarity. Disrupting NF2 affects YAP1 localization and cell structure, impacting tissue development.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Biology
Background:
- The Hippo pathway regulates cell proliferation and differentiation.
- Scaffold proteins like neurofibromin 2 (NF2) link cell polarity to Hippo pathway activity.
- Mechanisms of Hippo pathway regulation by cell polarity in outer cells are not fully understood.
Purpose of the Study:
- To investigate how NF2 subcellular localization impacts Hippo pathway activity and cell polarity.
- To elucidate the role of NF2 in establishing outer cell characteristics during early embryogenesis.
Main Methods:
- Generated artificial Nf2 mutants (L64P) in the N-terminal FERM domain.
- Assessed Hippo pathway activity by examining YAP1 subcellular localization in early embryos.
- Analyzed the localization of LATS2 and ezrin in polar cells.
Main Results:
- The L64P-Nf2 mutant impaired NF2 membrane localization, causing YAP1 to translocate to the cytoplasm.
- Apical centralization of LATS2 and ezrin in polar cells was disrupted by L64P-Nf2 expression.
- Lats2 mutants (L83K) inhibited YAP1 nuclear translocation.
Conclusions:
- NF2's subcellular localization is critical for establishing cell polarity through ezrin centralization.
- The Hippo pathway is modulated by the coordinated action of NF2, LATS2, and ezrin during cell polarization.
- This study reveals novel insights into cell-surface component orchestration in Hippo pathway regulation.
