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1 Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
2 Molecular Genetics Unit, DIBIT, Università Vita-Salute S. Raffaele, via Olgettina 58, 20132 Milan, Italy
3 Mammalian Genetics Unit, MRC, Harwell, Oxon OX11 0RD, UK
4 Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
* Present address: Department of Developmental Neurobiology, Instituto Cajal, CSIC, Av. Doctor Arce 37, 28002 Madrid, Spain
Present address: The Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridgshire CB10 1SA, UK
Author for correspondence (e-mail: rek{at}stowers-institute.org)
Accepted June 22, 2001
During development of the vertebrate hindbrain, Hox genes play multiples roles in the segmental processes that regulate anteroposterior (AP) patterning. Paralogous Hox genes, such as Hoxa3, Hoxb3 and Hoxd3, generally have very similar patterns of expression, and gene targeting experiments have shown that members of paralogy group 3 can functionally compensate for each other. Hence, distinct functions for individual members of this family may primarily depend upon differences in their expression domains. The earliest domains of expression of the Hoxa3 and Hoxb3 genes in hindbrain rhombomeric (r) segments are transiently regulated by kreisler, a conserved Maf b-Zip protein, but the mechanisms that maintain expression in later stages are unknown. In this study, we have compared the segmental expression and regulation of Hoxa3 and Hoxb3 in mouse and chick embryos to investigate how they are controlled after initial activation. We found that the patterns of Hoxa3 and Hoxb3 expression in r5 and r6 in later stages during mouse and chick hindbrain development were differentially regulated. Hoxa3 expression was maintained in r5 and r6, while Hoxb3 was downregulated. Regulatory comparisons of cis-elements from the chick and mouse Hoxa3 locus in both transgenic mouse and chick embryos have identified a conserved enhancer that mediates the late phase of Hoxa3 expression through a conserved auto/cross-regulatory loop. This block of similarity is also present in the human and horn shark loci, and contains two bipartite Hox/Pbx-binding sites that are necessary for its in vivo activity in the hindbrain. These HOX/PBC sites are positioned near a conserved kreisler-binding site (KrA) that is involved in activating early expression in r5 and r6, but their activity is independent of kreisler. This work demonstrates that separate elements are involved in initiating and maintaining Hoxa3 expression during hindbrain segmentation, and that it is regulated in a manner different from Hoxb3 in later stages. Together, these findings add further strength to the emerging importance of positive auto- and cross-regulatory interactions between Hox genes as a general mechanism for maintaining their correct spatial patterns in the vertebrate nervous system.
Key words: Hox genes, Hindbrain, Segmentation, Transgenic mice, Chick embryos, Auto/cross-regulation, Pbx, Meis
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  S. Bel-Vialar, N. Itasaki, and R. Krumlauf Initiating Hox gene expression: in the early chick neural tube differential sensitivity to FGF and RA signaling subdivides the HoxB genes in two distinct groups Development, March 13, 2003; 129(22): 5103 - 5115. [Abstract] [Full Text] [PDF]
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