Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb.
To date, only the five most posterior groups of Hox genes, Hox9-Hox13, have demonstrated loss-of-function roles in limb patterning. Individual paralog groups control proximodistal patterning of the limb skeletal elements. Hox9 genes also initiate the onset of Hand2 expression in the posterior forelimb compartment, and collectively, the posterior HoxA/D genes maintain posterior Sonic Hedgehog (Shh) expression. Here we show that an anterior Hox paralog group, Hox5, is required for forelimb anterior patterning. Deletion of all three Hox5 genes (Hoxa5, Hoxb5, and Hoxc5) leads to anterior forelimb defects resulting from derepression of Shh expression. The phenotype requires the loss of all three Hox5 genes, demonstrating the high level of redundancy in this Hox paralogous group. Further analyses reveal that Hox5 interacts with promyelocytic leukemia zinc finger biochemically and genetically to restrict Shh expression. These findings, along with previous reports showing that point mutations in the Shh limb enhancer lead to similar anterior limb defects, highlight the importance of Shh repression for proper patterning of the vertebrate limb.
Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI 48109.
Ben
B
Xu
Steven M
SM
Hrycaj
Daniel C
DC
McIntyre
Nicholas C
NC
Baker
Jun K
JK
Takeuchi
Lucie
L
Jeannotte
Zachary B
ZB
Gaber
Bennett G
BG
Novitch
Deneen M
DM
Wellik
D000818:Animals; D005552:Forelimb / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D038081:Organogenesis / Q000502:physiology*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*
D053823:Hedgehog Proteins; C489520:Hoxd4 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C465570:Shh protein, mouse; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse
anteroposterior limb patterning; gene interactions; limb development; mouse developmental genetics; organogenesis