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tailless REGULATION Targets of Activity In the anterior domain Tailless exerts a repressive effect on the expression of fushi tarazu, hunchback, and Deformed. In its posterior domain of action, Tailless is responsible for the establishment ofAbdominal-B expression and demarcating the posterior boundary of the initial domain of expression of Ultrabithorax (Reinitz, 1990). Cis-acting elements for the expression of buttonhead head stripe expression are contained in a 1 kb DNA fragment, located about 3 kb upstream of the promoter, The four maternal coordinate systems are necessary for correct btd head stripe expression, most likely by acting through the 1 kb cis-acting control region. Expression of the btd head stripe depends on bicoid. bcd-dependent activation also involves the activity of the morphogens of the posterior and dorsoventral systems, hunchback and dorsal, respectively, which act together to control the spatial limits of the expression domain. Finally, tailless, a torso dependent repressor of btd, takes part in the regulation of btd head stripe expression by enhancing activation at low levels of activity and repression at high levels of activity (Wimmer, 1995).The terminal genes of Drosophila specify non-segmented regions of the larval body that are derived from the anterior and posterior regions of the early embryo. Terminal class genes include both maternal-effect loci (typified by the receptor tyrosine kinase Torso) that encode components of a signal transduction cascade and zygotic genes (e.g. Tailless and Huckebein) that are transcribed at the poles of the embryo in response to the local activation of the pathway. A zygotic gene, bowel, has been characterized that is a zinc finger homolog of the pair-rule segmentation gene odd-skipped. bowel transcripts are initially expressed at both poles of the blastoderm embryo and in a single cephalic stripe. This pattern depends upon Torso and Tailless activity, but is not affected in huckebein mutants. Five mutations that affect the Bowel protein were isolated and sequenced, including a nonsense mutation upstream of the zinc fingers and a missense mutation in a putative zinc-chelating residue. bowel mutants die as late embryos with defects in terminal derivatives including the hindgut and proventriculus. These results indicate that the developmental roles of odd-skipped and bowel have diverged substantially, and that bowel represents a new member of the terminal hierarchy that acts downstream of tailless and mediates a subset of tailless functions in the posterior of the embryo (Wang, 1996).The expression of the pair-rule gene hairy (h) in seven evenly spaced stripes along the longitudinal axis of the Drosophila blastoderm embryo ismediated by a modular array of separate stripe enhancer elements. The minimal enhancer element, which generates reporter geneexpression in place of the most posterior h stripe 7 (h7-element), contains a dense array of binding sites for factors providing thetrans-acting control of h stripe 7 expression as revealed by genetic analyses. The stripe seven enhancer is found in a minimal 932 bp region from a 1.5 kb DNA fragment of the h upstream region. The h7-element mediates position-dependent geneexpression by sensing region-specific combinations and concentrations of both the maternal homeodomain transcriptional activators,Caudal and Bicoid, and of transcriptional repressors encoded by locally expressed zygotic gap genes. Zygotic caudal expression is not required for activation. Caudal and Bicoid, which formcomplementing concentration gradients along the longitudinal axis of the embryo, function as redundant activators, indicating that theanterior determinant Bicoid is able to activate gene expression in the most posterior region of the embryo. The spatial limits of the hstripe-7 domain are brought about by the local activities of repressors that prevent activation. The spatial limit of h7 is significantly altered in the gap mutants tailless, knirps and kruppel, but not in embryos lacking either hunchback, giant or huckebein. There are seven binding sites for Bcd, twenty-three for caudal, five for Kruppel, fourteen for Knirps, eight for Hunchback and five for Tailless. In the absence of both cad and bcd, activation still occurs. Thus, a third activator, likely to be Kr, must function in such embryos. It is thought that Kr acts as both a repressor and an activator within the h7 element depending on its concentration. The posterior border is set in response to Tll activity under the control of the terminal maternal organizer system. The anterior border of the expression domain is due to repression in response to Kni. The results suggest that the gradientsof Bicoid and Caudal combine their activities to activate segmentation genes along the entire axis of the embryo (La Rosee, 1997). Drosophila pair-rule gene expression, in an array of seven evenly spaced stripes along theanterior-posterior axis of the blastoderm embryo, is controlled by distinct cis-acting stripe elements. Inthe anterior region, such elements mediate transcriptional activation in response to (1) the maternalconcentration gradient of the anterior determinant Bicoid and (2) repression by spatially distinct activitiesof zygotic gap genes. In the posterior region, activation of hairy stripe 6 has been shown to depend onthe activity of the gap gene knirps, suggesting that posterior stripe expression is exclusively controlledby zygotic regulators. The zygotic activation of hairy stripe 6 expression is precededby activation in response to maternal caudal activity. Thus, transcriptional activation of posterior stripeexpression is likely to be controlled by maternal and zygotic factors as has been observed for anteriorstripes. To establish the potential of Cad and Kni to interact with the cis-acting DNA that mediates hairy stripe 6-like expression in the embryo, in vitro footprinting experiments were performed with the 532 bp hairy stripe 6-element DNA. Cad and Kni bind to thirty six in vitro binding sites, some of which overlap, throughout the element. The sequence of the Cad and Kni binding sites matches the consensus described for each of the two proteins. Most of the potential Cad and Kni binding sites are close to or overlapped by binding sites for Kruppel (eight sites), Hunchback (eight sites), and Tailless (five sites). Tests using fragments of the 532 bp enhancer and of another element, 284-HT, show that sequences mediating activation of reporter expression are not maintained within a minimal activation element but instead are dispersed throughout the enhancer (Hader, 1998). A 500 bpDNA fragment from an ehancer region of Ultrabithorax, approximately 30 kb away from the structural gene,contains one of the distant UBX regulatory elements (bx region enhancer, BRE). Hunchback repressesUBX expression directly by binding to BRE and probably other Ubx regulatory elements. Inaddition, the BRE pattern requires input from other segmentation genes, among them tailless andfushi tarazu but not Krüppel and knirps (Qian, 1993).The effects of mutations in five anterior gap genes (hkb, tll, otd, ems and btd) on the spatialexpression of the segment polarity genes, wg and hh, have been analyzed at the late blastoderm stageand during subsequent development. Both wg and hh are normally expressed at blastoderm stagein two broad domains anterior to the segmental stripes of the trunk region. At the blastoderm stage,each gap gene acts specifically to regulate the expression of either wg or hh in the anterior cephalicregion: hkb, otd and btd regulate the anterior blastoderm expression of wg, while tll and emsregulate hh blastoderm expression. (Mohler, 1995). The tll gene has negative effects on gap genes knirps, Krüppel and giant, setting up their posterior borders of expression (Huelskamp, 1991).The closely linked POU domain genes pdm-1 and pdm-2 are first expressed early duringcellularization in the presumptive abdomen in a broad domain that soon resolves into two stripes.This expression pattern is regulated by the same mechanisms that define gap gene expressiondomains. The borders of pdm-1 expression are set by the terminal system genes torso and tailless,and the gradient morphogen encoded by hunchback. The resolution into two stripes is controlledby the gap gene knirps (Cockerill, 1993). Tailless activates specific domains of expression of caudal and forkhead and Krüppel (Mlodzik, 1987 and Gaul, 1991). Terminal gap genes tailless and huckebein direct theformation of the posterior hunchback stripe. The anterior border of the posterior hb stripeis determined by TLL concentration in a manner analogous to the activation of anterior hb expressionby Bicoid (Margolis, 1995). Tailless protein activates the seventh stripe of expression of at least three pair-rule genes: even-skipped, hairy and fushi tarazu. tailless alleles can be placed in the same order of phenotypic strength on the basis of the deletion of either external structures (A8 and anal pads) or an internal structure (hindugt). Furthermore, different tll alleles result in a gradation in levels of T-related gene expression and these levels of Trg expression are correlated with the size of the differentiated hindgut (references in Diaz, 1996).Tailless is required for the normal pattern of the paired protein in the embryo. Specifically, stripes 6 and 7 are broader and shift posteriorly while in tailless mutants stripe 8 never appears (Gutjahr, 1993).There are several distinct phases of runt expression in the early embryo. Each phase depends on a different set of regulators. The first phase of expression is a broad-field of mRNA accumulation in the central regions of syncytial blastoderm stage embryos. This pattern is due to terminal repression by the anterior and terminal maternalsystems. The effect of the terminal system, even at this early stage, is mediated by two zygotic gapgenes, tailless and huckebein. A 7 stripe pattern of Runt mRNA accumulation emerges during the process of cellularization. The initial formation of this pattern depends on position-specificrepression by zygotic gap genes (Klingler, 1993).Ectopic expression of the pair-rule gene runt in the anterior end of the Drosophila embryo antagonizestranscriptional activation of the head gap gene orthodenticle (otd) by the anterior morphogen bicoid.The relevance of runt's activity as a repressor of otd in normal Drosophilaembryogenesis has been investigated. otd expression is activated in the posterior region of embryos that are mutant for runt.This posterior expression domain of otd depends on the activity of the orphan nuclear receptor proteinTailless. Repression of otd by runt does not require the conserved VVVRPY motif, which mediatesinteraction between Runt and the co-repressor protein Groucho. It is speculated that the genetic interactions between runt and tll involve physical interactions between the two proteins. It is interesting to note that interactions between Runt and another orphan nuclear receptor protein, Ftz-F1 have been invoked to explain runt's regulation of the pair-rule gene fushi tarazu. However, in this case runt functions to activate, rather than repress Ftz-F1 dependent transcription. It will be interesting to determine if there are binding sites for Tll that are essential for the activation of otd in the posterior region and whether these sites respond to the repressive activity of runt. It is noted that the activity of tll is necessary, but not sufficient for otd expression in the posterior region of the embryo.The observed functional interactionsbetween runt and tailless on otd expression may indicate there are other contexts where members ofthese two families of transcriptional regulators interact to regulate gene expression during development (Tsai, 1998).An effect on the early stripe of Goosecoid expression is observed in sloppy-paired, orthodenticle, tailless and decapentaplegic mutants. Both slp and otd affect Gsc in a similar way: the early stripe of Gsc appears normally but at the end of the cellularization stage, there is no reinforcement of its expression and it is prematurely lost. dpp is necessary to bring aboud Gsc repression in the dorsal-most region of the embryo, while tll is required to promote Gsc expression in the lateral region, or to prevent its repression by the dorsoventral patterning system (Goriely, 1996). Tailless activates the Drosophila T-related gene, the homolog of vertebrate Brachyury gene (Kispert, 1994).By examining expression of arc in different mutant embryos,it was determined that transcription factors known tobe required for patterning and maintenance of variousdeveloping epithelia control arc expression in those domains. tll and hkb, whichare required to pattern the posterior 15% of the embryo, control arc expressionin the posterior midgut primordium. fkh, which appears toact as a maintenance, or permissive, transcription factor, isrequired for expression of arc throughout the gut. byn,which is required for hindgut development and specifies itscentral domain (the large intestine),controls expression of arc in the elongating hindgut. Kr andcut, required for evagination and extension of the Malpighiantubule budscontrol expression of arc in the tubule primordia (Liu, 2000).Unlike gap genes in the trunk region of Drosophila embryos, gap genes in the head were presumed not to regulate each other's transcription. However, in tailless loss-of-function mutants the empty spiracles expression domain in the head expands, whereas it retracts in tllgain-of-function embryos. A 304bp element in the ems-enhanceris sufficient to drive expression in the head and brain; it contains two Tll and two Bcd binding sites. Transgenic reporter gene lines containing mutations of the Tll binding sites demonstrate that tll directly inhibits the expression of ems in the early embryonic head and the protocerebral brain anlage. These results are the first demonstration of direct transcriptional regulation between gap genes in the head (Hartmann, 2002).The protein product of the anterior maternal system gene,bcd, is a morphogen and differentially directs the expressionpattern of the first zygotic genes in the anterior region of theembryo. This isthought to be achieved by differences in the affinity of theBcd binding sites within the promotors of these zygoticgenes. Thus, the broadly expressed gap gene hb containsstrong Bcd binding sites and requires only a low level ofBcd for its activation. In contrast, the cephalic gap genes ems, orthodenticle (otd), buttonhead (btd) and sloppy paired (slp), whose expression patterns are restricted to anterior regions of the embryo, are presumed to contain low affinity Bcd binding sites requiring high levels of Bcd for their activation. So far,Bcd binding sites have only been mapped for otd, and itis assumed that these binding sites have a low affinity forBcd. A 304 bp fragment of the ems enhancer that issufficient to generate an ems like expression pattern in thehead primordium contains two Bcd consensus sites thatbind Bcd in vitro. These sites in the ems enhancer elementare medium affinity binding sites. This might reflect the factthat ems is expressed posterior to otd and thus requires alower threshold level of Bcd for its activation compared tootd. Mutations of these Bcd binding sites show that theyare also essential for the in vivo function of this enhancerelement during early head patterning. This suggests thatBcd, or a protein with similar binding specificity, directlyactivates ems expression in the head primordium. The onlyknown protein with a similar binding specificity as Bcd is Otd. Since ems activation is independent of otd, it is posited that Bcd directly regulates early ems expression (Hartmann, 2002).Embryos lacking both maternal and zygotic hb display a reductionand an anterior shift of ems and btd expression at the blastoderm stage. Thus, it has been proposed that head-specific emsexpression at the blastoderm stage requires synergistic activationby bcd and hb. However, no hb consensus site could be detected within the 304 bp enhancer element. It cannot be excluded that hb binding sites exist in the ems enhancer outside this element. However, the results suggest that hb plays a relatively minor role in ems expression control in the head and brain (Hartmann, 2002). If Bcd is responsible for activating ems and determiningits posterior expression border, how is the anterior expressionborder of ems established? This study provides severallines of evidence that indicate that the anterior border ofems expression is set up by repression from another gapgene, namely tll. Thus, in tll mutants, ems expressionexpands anteriorly, which suggests that the absence of tllresults in a derepression of ems transcription in this domain.Moreover, two consensus tll target sites have been identified inthe ems enhancer that bind Tll in vitro and which areessential for the function of this element in vivo. Mutationof these Tll binding sites results in an anterior expansion ofems reporter gene expression in the head primordium in amanner similar to the tll loss-of-function phenotype. Therefore,it is proposed that Tll directly inhibits ems expressionin the head primordium (Hartmann, 2002).The gap genes that are expressed in the trunk region ofthe embryo tightly regulate each others expression domainsand show only little overlap. Most of the head gap genes, on the contrary,were expressed in largely overlapping domains and were sofar presumed not to interact with each other, butcan be regulated by terminal gap genes. Otd is regulated bythe gap gene huckebein and btd is underthe control of tll (Hartmann, 2002 and references therein).This study gives another example of two gap genes in thehead, tll and ems, which behave like gap genes in the trunk,in that they are expressed in nonoverlapping domains anddirectly interact with each other. It remains to be seen whether ems in turn acts as repressor of tll transcription (Hartmann, 2002).Interestingly, the 304 bp region in the ems enhancer,which is necessary and sufficient to drive express