Neuronal Basic Helix–Loop–Helix Proteins Neurod2/6 Regulate Cortical Commissure Formation Before Midline Interactions
The Journal of Neuroscience, January 9, 2013 • 33(2):641–651 • 641 Development/Plasticity/Repair Neuronal Basic Helix–Loop–Helix Proteins Neurod2/6 Regulate Cortical Commissure Formation before Midline Interactions Ingo Bormuth,1,2* Kuo Yan,2* Tomoko Yonemasu,1 Maike Gummert,1 Mingyue Zhang,3 Sven Wichert,1 Olga Grishina,2* Alexander Pieper,1 Weiqi Zhang,3 Sandra Goebbels,1 Victor Tarabykin,2 Klaus-Armin Nave,1 and Markus H. Schwab1 1Max Planck Institute of Experimental Medicine, Department of Neurogenetics, D-37075 Go¨ttingen, Germany, 2Charite´–Universita¨tsmedizin Berlin, Institute of Cell Biology and Neurobiology, NeuroCure Cluster of Excellence, D-10115 Berlin, Germany, and 3University of Mu¨nster, Department of Psychiatry, Laboratory of Molecular Psychiatry, D-48149 Mu¨nster, Germany Establishment of long-range fiber tracts by neocortical projection neurons is fundamental for higher brain functions. The molecular control of axon tract formation, however, is still poorly understood. Here, we have identified basic helix–loop–helix (bHLH) transcrip- tion factors Neurod2 and Neurod6 as key regulators of fasciculation and targeted axogenesis in the mouse neocortex. In Neurod2/6 double-mutant mice, callosal axons lack expression of the cell adhesion molecule Contactin2, defasciculate in the subventricular zone, and fail to grow toward the midline without forming Probst bundles. Instead, mutant axons overexpress Robo1 and follow random trajectoriesintotheipsilateralcortex.Incontrasttolong-rangeaxogenesis,generationandmaintenanceofpyramidalneuronsandinitial axon outgrowth are grossly normal, suggesting that these processes are under distinct transcriptional control. Our findings define a new stage in corpus callosum development and demonstrate that neocortical projection neurons require transcriptional specification by neuronal bHLH proteins to execute an intrinsic program of remote connectivity.
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