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Spatially dependent dynamic MAPK modulation by the Nde1-Lis1-Brap complex patterns mammalian CNS.

Alison A Lanctot1, Chian-Yu Peng, Ashley S Pawlisz

  • 1Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA.

Developmental Cell
|May 16, 2013
PubMed
Summary

The Nde1-Lis1 complex controls cell fate in CNS development by modulating MAPK signaling. This complex ensures proper cell proliferation and differentiation based on location relative to signaling centers.

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Biology

Background:

  • Central nervous system (CNS) development requires precise regulation of neural progenitor cell proliferation and differentiation.
  • Neural progenitors respond to complex signaling gradients from midline centers, making unique cell fate decisions.
  • The Nde1-Lis1 complex is implicated in cell fate determination during CNS development.

Purpose of the Study:

  • To investigate the role of the Nde1-Lis1 complex in mediating spatially dependent cell fate decisions in the developing CNS.
  • To elucidate the molecular mechanisms by which Nde1-Lis1 regulates responses to mitogenic signaling gradients.

Main Methods:

  • Analysis of Nde1-Lis1 double-mutant mice to assess CNS development.
  • Investigation of the interaction between Lis1 and Brap, a MAPK signaling modulator.
  • Examination of mitogen-activated protein kinase (MAPK) pathway components, including Ksr.

Main Results:

  • Nde1-Lis1 deficiency leads to spatially distinct defects: failure of self-renewal in distant cells and overproliferation in cells near signaling centers.
  • A direct interaction between Lis1 and Brap mediates differential responses to mitogenic gradients.
  • Nde1-Lis1 deficiency alters MAPK scaffold Ksr localization and causes MAPK hyperactivation in a spatially dependent manner.
  • Epistasis analyses confirm synergistic roles for Brap and Lis1.

Conclusions:

  • The Nde1-Lis1 complex, in conjunction with Brap, regulates the dynamic MAPK signaling threshold in a spatially dependent manner.
  • This molecular complex is crucial for precise control of neural progenitor proliferation and differentiation during CNS development.