Disruption of Krox20-Nab interaction in the mouse leads to peripheral neuropathy with biphasic evolution.
Krox20/Egr2 is a zinc finger transcription factor that plays essential roles in several developmental processes, including peripheral nervous system myelination by Schwann cells, where it acts as a master gene regulator. Krox20 is known to interact with cofactors of the Nab family and a mutation affecting isoleucine 268, which prevents this interaction, has been shown to result in congenital hypomyelinating neuropathy in humans. To further investigate the role of this interaction, we have introduced such a mutation, Krox20(I268F), in the mouse germ line. Clinical, immunohistochemical, and ultrastructural analyses of the homozygous mutants reveal that they develop a severe hypomyelination phenotype that mimics the human syndrome. Furthermore, a time-course analysis of the disease indicates that it follows a biphasic evolution, the hypomyelination phase being followed by a dramatic demyelination. Although for the regulation of most analyzed Krox20 target genes the mutation behaves as a loss of function, this is not the case for a few of them. This differential effect indicates that the molecular function of the Krox20-Nab interaction is target dependent and might explain the degradation of the residual myelin, because of imbalances in its composition. In conclusion, this work provides a novel and useful model for severe human peripheral neuropathies.
Inserm U784, 75230 Paris Cedex 05, France.
Anne
A
Desmazières
Laurence
L
Decker
Jean-Michel
JM
Vallat
Patrick
P
Charnay
Pascale
P
Gilardi-Hebenstreit
D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051767:Early Growth Response Protein 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000473:pathology / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
D051767:Early Growth Response Protein 2; C490624:Nab1 protein, mouse; C099945:Nab2 protein, mouse; D009363:Neoplasm Proteins; D012097:Repressor Proteins