Top 15 articles on Hox function- Part II
So moving further into the series of “Top 15 articles on Hox function” ( In case you missed, read part I here ).
6) This article in fact set the trend for many to follow and one of my all time favorite- Steve cohen lab’s showed for the very first time that Distalless (dll) is a direct hox target and repression of this gene by Hox is vital for abdominal specification in fly. Vachon et al. had identified a minimal cis-regulatory enhancer element that directs Dll expression in the larval leg primordia and it is where Hox protein binds to silence its expression in abdomen. Further they mutated these Hox binding sites in enhancer and tested in transgenic assays. Results showed that mutating these sites eliminates BX-C protein binding and renders the element insensitive to BX-C-mediated repression in vivo.
Homeotic genes of the Bithorax complex repress limb development in the abdomen of the Drosophila embryo through the target gene Distal-less.
Vachon G, Cohen B, Pfeifle C, McGuffin ME, Botas J, Cohen SM.
Cell. 1992 Oct 30;71(3):437-50.
7) Maria Capovilla et al. reported another direct target of Hox gene ( Ubx and Abd-A) in article published 1994 cell issue. Hox genes Ubx ,abd-A and member of tgf-beta family of proteins ,decapentaplegic (dpp) are required for the formation of second mid gut formation in Drosophila. They identified a 674 bp enhancer of dpp controlling its expression in the second constriction domain of the visceral mesoderm. This enhancer was shown to contain sites for Ubx , abd-A and regulated positively by Ubx but negatively by abd-A. By generating complementary alterations of the binding sites and the binding specificity of UBX, they show that Ubx directly regulates dpp expression.
Direct regulation of decapentaplegic by Ultrabithorax and its role in Drosophila midgut morphogenesis.
Capovilla M, Brandt M, Botas J.
Cell. 1994 Feb 11;76(3):461-75.
8 ) This article from Richard mann’s lab can be considered as one the finest work in the field of Hox function ,where they excellently shows the involvement of segmentation genes in regulation of distalless (dll) gene. Brian gebelein and colleagues have shown that minimal enhancer of dll ,which recapitulates the accurate Dll-like expression in the thorax ,contains binding sites for segmantaion genes engrailed , sloppy paired apart from previously known sites for Hox,extradenticle and homothorax (known co factors for Hox genes).They further tested the involvement of segmentation genes by performing thorough mutagenesis of enhancer ,where they saw compartment specific derepression in abdomen when binding sites of engrailed or sloppy paired are mutated.
Direct integration of Hox and segmentation gene inputs during Drosophila development.Gebelein B, McKay DJ, Mann RS.
Nature. 2004 Oct 7;431(7009):653-9.
9) It was clear that Hox proteins mostly don’t act alone but instead takes the help of co factors while regulating the downstream target genes. One of the well known, co factor in Drosophila is extradenticle (exd), a TALE class of protein and its homolog in vertebrates is PBC class. It is very characterized that Hox interacts with extradenticle through a short conserved motif lying upstream of homeodomain called “Hexapeptide” or YPWM motif. But while regulating dll ,Hox proteins seems to be bypass the requirement of classical hexapetide motif for recruiting exd. Samir merabet et al . identified in the Drosophila Ultrabithorax (Ubx) protein a short motif responsible for an alternative mode of Exd recruitment. This motif is called “UBDA” motif (named UBDA because this motif is found only in Hox proteins UBX and abd-A, which is a short conserved stretch of amino acids “KLENEQ” in C-terminus of protein. This finding highlights that the Hox protein Ubx has multiple ways to interact with the Exd
cofactor and suggests that flexibility in Hox–PBC contacts contributes to specify and diversify Hox protein function.
A unique Extradenticle recruitment mode in the Drosophila Hox protein Ultrabithorax.
Merabet S, Saadaoui M, Sambrani N, Hudry B, Pradel J, Affolter M, Graba Y.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16946-51.
10) This work from the lab of Sean carroll is arguably the best study published so far on how gene regulation differs in homologous structures like wing and haltere. Mutations of Ubx result in transformation of the dorsal appendages of the third thoracic segment (haltere ) into their counterparts on the second thoracic segment(Wing).
Results from the study obtained by virtue of some excellent genetic experiments indicate that Ubx down regulates DV morphogen wingless in posterior compartment of haltere and at also acts downstream of dpp pathway by repressing splat (r).The major contribution of ubx for shaping haltere comes from repressing Quadrant enhancer of vestegial (Pro wing gene).The significant outcome of this work is that Ubx represses wing development through the independent regulation of target genes at multiple levels of regulatory hierarchies,which could be the case for other Hox genes regulating homologous structures in other animals.
Ultrabithorax regulates genes at several levels of the wing-patterning hierarchy to shape the development of the Drosophila haltere
Scott D. Weatherbee, Georg Halder, Jaeseob Kim, Angela Hudson, and Sean Carroll
Genes Dev. 1998 12: 1474-1482
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