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Neuronal basic helix-loop-helix proteins Neurod2/6 regulate cortical commissure formation before midline

Ingo Bormuth1, Kuo Yan, Tomoko Yonemasu

  • 1Max Planck Institute of Experimental Medicine, Department of Neurogenetics, D-37075 Göttingen, Germany.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
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Basic helix-loop-helix transcription factors Neurod2 and Neurod6 regulate axon tract formation in the mouse neocortex. Loss of Neurod2/6 disrupts corpus callosum development, affecting long-range connectivity crucial for brain function.

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Molecular Biology

Background:

  • Long-range fiber tracts are essential for higher brain functions.
  • The molecular mechanisms governing axon tract formation are not fully understood.

Purpose of the Study:

  • To identify key regulators of axon fasciculation and targeted axogenesis in the neocortex.
  • To elucidate the role of basic helix-loop-helix (bHLH) transcription factors in corpus callosum development.

Main Methods:

  • Utilized Neurod2/6 double-mutant mice to study gene function.
  • Analyzed expression of cell adhesion molecules (e.g., Contactin2) and axon guidance receptors (e.g., Robo1).
  • Examined neocortical projection neuron development, including fasciculation and midline targeting.

Main Results:

  • Neurod2 and Neurod6 are identified as critical regulators of neocortical axon tract formation.
  • In Neurod2/6 mutants, callosal axons lose Contactin2, defasciculate, and fail to reach the midline, bypassing Probst bundle formation.
  • Mutant axons exhibit increased Robo1 expression and aberrant ipsilateral trajectories.
  • Pyramidal neuron generation and initial axon outgrowth remain largely unaffected, indicating distinct regulatory control.

Conclusions:

  • Neuronal bHLH proteins, specifically Neurod2 and Neurod6, are essential for specifying long-range connectivity in neocortical projection neurons.
  • These factors control a critical stage in corpus callosum development, enabling the execution of an intrinsic program for remote axonal connections.