The enormous diversity in body plan among the various organisms in animal kingdom is partly contributed by the Hox genes.Hox proteins regulate gene expression in different ways and thereby generating different body plans.Most of the organisms on earth have one or more clusters of Hox genes.These Hox genes pattern different segment and thus gives a unique identity by altering their expression patterns,their targets and their functional domains.
As you know hox genes dont act alone,mostly they function with other co factors.But the problem here is same co factor or factors are used for both activating and repressing a particular target gene.For example Hox protein Ultrabithorax(ubx) combines with extradenticle (exd) represses Distalless (a homeobox genes responsible for limb development throughout animal kingdom) in abdominal region of drosophila and and same two proteins activate Decapentaplegic (dpp) in the visceral mesoderm.
The solution for this could lie at the enhancer sequences where these proteins bind (Hox and cofactors) and some more cofactors are employed in the complex for regulating the gene expression.Some very brilliant work from the lab of Richard mann from Columbia university proves that Hox genes employs more cofactors(other than famous exdtradenticle and homothorax) and sequences at the target site also plays essential roles in regulation of distalless(dll) gene in abdomen of fruit fly.
Distalless (Dll) is a Hox target gene that is required for leg development in Drosophila.It is expressed in three thoracic segments but repressed in abdomen.One important morphological difference in animal kingdom is presence and absence of limbs in arthropoda.Dll is marker for limb primodium throughout animal kingdom.Drosophila has evolved a mechanism to repress limb development in abdomen.
A cis regulatory element called DMX derived from dll gene drives accurate dll likes expression in thorax.
DMX is composed of a large activator element (DMXact) and a 57-base-pair (bp) repressor element which harbors the binding sites for Hox ,exd,hth ,engrailed and sloppy paired .
The abdominal Hox genes Ultrabithorax (Ubx) and abdominalA (abdA) directly repress Dll in a compartment wise manner, thereby blocking leg development in the abdomen.where as thoracic Hox gene antennapedia fails to do so.Gebelein et al through thier artcle in Dev cell 2002 showed that exd and hth selectively enhances ubx specificity towards dll regulatory element but not antennapedia binding .
CURRENT MODEL :
According to current model of dll regulation two bithorax genes ubx and abdA bind directly to dll regulatory region and brings in the repression in a compartment wise manner from A1 to A7.
Well known hox cofactors exd and hth are crucial part of this complex . The compartment wise repression of dll is possible by involvement of two segmentation genes engrailed and sloppy paired.
Its pretty well worked out that ubx in association with sloppy paired (segmentation gene specific to anetrior segment) ,exd and hth binds to their respective binding sites on DMXR and thus shuts off dll in anterior compartment . Engrailed the posterior specific segmentation gene along with exd and hth helps out abdA to repress dll in posterior compartment.
In this way ubx and adbA repress dll in abdomen .In contrast, the thoracic Hox protein Antennapedia (Antp) does not repress Dll as it does not bind DMX-R with high affinity in the presence or absence of Exd and Hth.They also propose involvement of known co repressor groucho in the complex as it can interact with engrailed and sloppy paired.To sum up the distalless regulation ,ubx/exd/hth complex might be required for target gene selection but binding sites in the enhancer region of dll for engrailed and sloppy paired are crucial for repression as they could recruit corepressor like groucho and bring in repression.
Another important discovery in the regulation of dll came from Yacine Graba’s lab.They show that hexapeptide (YPWM) sequence is not used by ubx protein for making interactions with exd during dll repression. Ubx recruits exd using another evolutionary conserved motif called as UBDA motif (KELNEQ),which is present in C-terminus of ubx and abdA Hox proteins. 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.
1) Gebelein B, Culi J, Ryoo HD, Zhang W, Mann RS.
Specificity of Distalless repression and limb primordia development by abdominal Hox proteins.
Dev Cell. 2002 Oct;3(4):487-98
2) Gebelein B, McKay DJ, Mann RS.
Direct integration of Hox and segmentation gene inputs during Drosophila development.
Nature. 2004 Oct 7;431(7009):653-9
3) Merabet S, Saadaoui M, Sambrani N, Hudry B, Pradel J, Affolter M, Graba Y.
A unique Extradenticle recruitment mode in the Drosophila Hox protein Ultrabithorax.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16946-51