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SLK-dependent activation of ERMs controls LGN-NuMA localization and spindle orientation

Mickael Machicoane1, Cristina A de Frutos2, Jenny Fink3

  • 1Membrane Traffic and Cell Division Laboratory, Institut Pasteur, 75015 Paris, France Centre National de la Recherche Scientifique URA2582, 75015 Paris, France Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Institut de formation doctorale, 75252 Paris, France.

The Journal of Cell Biology
|June 25, 2014
PubMed

Insights

The membrane-actin linkers ezrin/radixin/moesin (ERMs) are activated at mitotic entry and crucial for guiding mitotic spindle orientation. Impairing ERM activation disrupts spindle orientation in mammalian cells and the developing brain.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Biophysics

Background:

  • Mitotic spindle orientation is essential for cell division and relies on interactions between spindle microtubules and the cell cortex.
  • F-actin and its associated proteins play a recently recognized role in this process.
  • The precise molecular mechanisms linking cortical components to spindle positioning are still being elucidated.

Purpose of the Study:

  • To investigate the role of membrane-actin linkers, specifically ezrin/radixin/moesin (ERMs), in regulating mitotic spindle orientation in mammalian cells.
  • To determine the molecular mechanisms by which ERM activation influences spindle positioning.
  • To assess the in vivo relevance of ERM function in spindle orientation during embryonic development.

Main Methods:

  • Utilized microfabricated adhesive substrates to precisely control cell division axis and study spindle orientation.
  • Investigated the activation of ERMs by Ste20-like kinase at mitotic entry.
  • Examined the effect of impaired ERM activation on spindle orientation in vivo using mouse embryonic neocortex apical progenitors.
  • Analyzed the molecular localization of key spindle orientation factors, LGN and NuMA, in response to ERM activation.

Main Results:

  • Demonstrated that ezrin/radixin/moesin (ERMs) are directly activated by a Ste20-like kinase upon mitotic entry in mammalian cells.
  • Showed that ERM activation is critical for guiding mitotic spindle orientation, as evidenced by experiments using controlled adhesive substrates.
  • Found that disrupting ERM activation in mouse embryonic neocortex apical progenitors leads to severe defects in spindle orientation in vivo.
  • Revealed that ERM activation promotes the polarized cortical localization of the leucine-glycine-asparagine repeat protein (LGN) and nuclear mitotic apparatus (NuMA) complex.

Conclusions:

  • Activated ERMs are key regulators of mitotic spindle orientation in mammalian cells.
  • ERM activation facilitates the proper localization of the LGN-NuMA force generator complex at the mitotic cortex.
  • This mechanism, involving ERMs and Gαi, is critical for ensuring correct spindle positioning during cell division and embryonic development.

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