HoxD cluster scanning deletions identify multiple defects leading to paralysis in the mouse mutant Ironside.
A spontaneous semidominant mutation (Ironside, Irn) was isolated in mice, leading to severe hindlimb paralysis following multiple deletions in cis at the HoxD locus. To understand its cellular and molecular etiology, we embarked on a comparative analysis using systematic HoxD cluster deletions, produced via targeted meiotic recombination (TAMERE). Different lines of mice were classified according to the severity of their paralyses, and subsequent analyses revealed that multiple causative factors were involved, alone or in combination, in the occurrence of this pathology. Among them are the loss of Hoxd10 function, the sum of remaining Hoxd gene activity, and the ectopic gain of function of the neighboring gene Evx2, all contributing to the mispositioning, the absence, or misidentification of specific lumbo-sacral pools of motoneurons, nerve root homeosis, and hindlimb innervation defects. These results highlight the importance of a systematic approach when studying such clustered gene families, and give insights into the function and regulation of Hox and Evx2 genes during early spinal cord development.
Tarchini
Basile
B
National Research Centre Frontiers in Genetics and Department of Zoology and Animal Biology, University of Geneva, 1211 Geneva 4, Switzerland.
Huynh
Thi Hanh Nguyen
TH
Cox
Greg A
GA
Duboule
Denis
D
D000015:Abnormalities, Multiple; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000294:innervation; D005121:Extremities / Q000293:injuries; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D008161:Lumbosacral Region; D051379:Mice; D009046:Motor Neurons / Q000473:pathology; D005810:Multigene Family; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010243:Paralysis / Q000209:etiology / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C486697:Hoxd1 protein, mouse; C490944:Hoxd10 protein, mouse; D014157:Transcription Factors; C074438:Evx2 protein, mouse