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The Journal of Neuroscience, December 15, 2004, 24(50):11215-11225; doi:10.1523/JNEUROSCI.3479-04.2004

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Development/Plasticity/Repair
CNS Myelin Paranodes Require Nkx6-2 Homeoprotein Transcriptional Activity for Normal Structure

Cherie Southwood,1,2 Chris He,1 James Garbern,2,4 John Kamholz,2,4 Edgardo Arroyo,5 and Alexander Gow1,2,3,4

1Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, New York, 10029, 2Center for Molecular Medicine and Genetics, 3Carman and Ann Adams Department of Pediatrics, 4Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, 48201, and 5Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, 19104

Homeodomain proteins play critical roles during development in cell fate determination and proliferation, but few studies have defined gene regulatory networks for this class of transcription factors in differentiated cells. Using a lacZ-knock-in strategy to ablate Nkx6-2, we find that the Nkx6-2 promoter is active embryonically in neuroblasts and postnatally in oligodendrocytes. In addition to neurological deficits, we find widespread ultrastructural abnormalities in CNS white matter and aberrant expression of three genes encoding a paranodal microtubule destabilizing protein, stathmin 1, and the paranodal cell adhesion molecules neurofascin and contactin. The involvement of these downstream proteins in cytoskeletal function and cell adhesion reveals mechanisms whereby Nkx6-2 directly or indirectly regulates axon- glial interactions at myelin paranodes. Nkx6-2 does not appear to be the central regulator of axoglial junction assembly; nonetheless, our data constitute the first evidence of such a regulatory network and provide novel insights into the mechanism and effector molecules that are involved.

Key words: targeted deletion; homeodomain; Nkx; cytoskeleton; auditory brainstem response; rotarod


Received Aug 23, 2004; revised October 11, 2004; accepted October 17, 2004.




This article has been cited by other articles:


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Proc. Natl. Acad. Sci. USAHome page
G. P. Garcia-Fresco, A. D. Sousa, A. M. Pillai, S. S. Moy, J. N. Crawley, L. Tessarollo, J. L. Dupree, and M. A. Bhat
Disruption of axo-glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons
PNAS, March 28, 2006; 103(13): 5137 - 5142.
[Abstract] [Full Text] [PDF]



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