CNS myelin paranodes require Nkx6-2 homeoprotein transcriptional activity for normal structure.
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.
Southwood
Cherie
C
Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, New York, 10029, USA.
He
Chris
C
Garbern
James
J
Kamholz
John
J
Arroyo
Edgardo
E
Gow
Alexander
A
D000818:Animals; D002490:Central Nervous System / Q000033:anatomy & histology / Q000378:metabolism* / Q000502:physiology; D003391:Cranial Nerves / Q000196:embryology / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000502:physiology*; D007365:Intercellular Junctions / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008868:Microtubule Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D011993:Recombinant Fusion Proteins; D045442:Rotarod Performance Test; D050777:Stathmin; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D018398:Homeodomain Proteins; D008868:Microtubule Proteins; D009419:Nerve Tissue Proteins; C117745:Nkx6-2 protein, mouse; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D050777:Stathmin; C493994:Stmn1 protein, mouse; D014157:Transcription Factors