tailless
Tailless mRNA is found in the blastoderm stage [Images]. Initial activation of tll transcription is in two mirror image symmetrical caps at the poles of the embryo. This expression resolves into a posterior cap and an anterior-dorsal stripe. tll is also expressed in brain neuroblasts (Pignoni, 1990).
Early tailless expression (blastoderm stage) covers the anlage of the entire brain. Beginning approximately with the onset of gastrulation, an anterior-dorsal region with a high expression level (called HL domain) can be distinguished from a posterior-ventral domain expressing tll at a somewhat lower level. The HL domain coincides with part of the central and anterior protocerebral neurectoderm. The low expression level LL domain covers the remaining part of the protocerebral neuroectoderm. orthodenticle is expressed in a circumferential domain of the cellular blastoderm but during gastrulation becomes restricted to a domain that encompasses most of the protocerebral neurectoderm and an adjacent part of the deuterocerebral neurectoderm. All neurobasts segregating from this domain transiently express otd during stages 10 and 11. buttonhead is initially expressed in a wide domain including the anlagen of the antennal, intercalary and mandibular segments, as well as the acron. With the beginning of gastrulation, expression disappears from most of the procephalon, except for small domains of the posterior part of the deuterocerebral and tritocerebral neurectoderm and a dorsoanterior patch that partially overlaps with the dorsoanterior protocerebrum. Both the late deutocerebral and tritocerebral btd domains contain few, if any neuroblasts. empty spiracles is in an asymmetric circumferential domain of the cellular blastoderm. During gastrulation, this pattern resolves into two stripes that occupy anterior portions of the deuterocerebral neuroectoderm and the mandibular metamere, respectively. In addition, a small circular domain corresponding to the tritocerebral neurectoderm appears ventral to the deuterocerebral stripe (Younossi-Hartenstein, 1997).
Loss of tll function results in the absence of all protocerebral neuroblasts and loss of all four coherent domains of Fas II expression in the protocerebrum. Also missing is the optic lobe. orthodenticle functions in a domain that includes a large part of the protocerebrum and a smaller part of the adjacent deuterocerebrum. Loss of otd results in loss of protocerebral P1, P2 and P4 coherent domains of Fas II expression. Also missing is a nerve that carries axons from the antennal organ. In buttonhead mutation the D/T cluster is missing; consequently a cervical connection is missing that normally sends nerves to the labral sensory organ, the hypopharyngeal sensory organ and the stomatogastric nervous system (Younossi-Hartenstein, 1997).
The Drosophila brain develops from the procephalic neurogenic region of the ectoderm. About 100 neural precursor cells (neuroblasts) delaminate from this region on either side in a reproducible spatiotemporal pattern. Neuroblast maps have been prepared from different stages of the early embryo (stages 9, 10 and 11, when the entire population of neuroblasts has formed), in which about 40 molecular markers representing the expression patterns of 34 different genes are linked to individual neuroblasts. In particular, a detailed description is presented of the spatiotemporal patterns of expression in the procephalic neuroectoderm and in the neuroblast layer of the gap genes empty spiracles, hunchback, huckebein, sloppy paired 1 and tailless; the homeotic gene labial; the early eye genes dachshund, eyeless and twin of eyeless; and several other marker genes (including castor, pdm1, fasciclin 2, klumpfuss, ladybird, runt and unplugged). Based on the combination of genes expressed, each brain neuroblast acquires a unique identity, and it is possible to follow the fate of individual neuroblasts through early neurogenesis. Furthermore, despite the highly derived patterns of expression in the procephalic segments, the co-expression of specific molecular markers discloses the existence of serially homologous neuroblasts in neuromeres of the ventral nerve cord and the brain. Taking into consideration that all brain neuroblasts are now assigned to particular neuromeres and individually identified by their unique gene expression, and that the genes found to be expressed are likely candidates for controlling the development of the respective neuroblasts, these data provide a basic framework for studying the mechanisms leading to pattern and cell diversity in the Drosophila brain, and for addressing those mechanisms that make the brain different from the truncal CNS (Urbach, 2003).
The cephalic gap genes are expressed in large domains of the procephalon and play a crucial role not only in the patterning of the peripheral ectoderm, but also in regionalizing the brain primordium. The segmental organization of the Drosophila brain is based on the expression pattern of segment polarity and DV patterning genes. To see whether the cephalic gap genes respect the neuromeric boundaries segment polarity and DV patterning genes, and to provide a basis for studying their potential role in the formation or specification of brain precursor cells, the expression was studied of orthodenticle, empty spiracles, sloppy paired 1, tailless, huckebein, and hunchback in the developing head ectoderm, as well as in the entire population of identified NBs during stages 9-11 (Urbach, 2003).
tailless (tll) has been shown to be expressed in an anterior horseshoe-shaped stripe in the cellular blastoderm, which after gastrulation shows a region of high ('HL domain') and a region of low level of tll expression ('LL domain'), and at stage 9 covers most of the protocerebral neuroectoderm. Using a tll-lacZ line at stage 9 tll expression has been found in the developing brain in most protocerebral NBs (except the dorsoposterior ones). During stages 9-11 tll-lacZ expression expands in the protocerebral neuroectoderm beyond the En-positive head spot (hs). By stage 11 it is detectable in all protocerebral NBs. In addition, tll-lacZ is found in some ventral and dorsal deutocerebral NBs, indicating that tll is not exclusively confined to protocerebral progenitors (Urbach, 2003).
The development of the head and tail regions of the Drosophila embryo is dependent upon the localized polar activation of Torso (Tor), a receptor tyrosine kinase that is uniformly distributed in the membrane of the developing embryo. Trunk (Trk), the proposed ligand for Tor, is secreted as an inactive precursor into the perivitelline fluid that lies between the embryonic membrane and the vitelline membrane (VM), the inner layer of the eggshell. The spatial regulation of Trk processing is thought to be mediated by the secreted product of the torsolike (tsl) gene, which is expressed during oogenesis by a specialized population of follicle cells present at the two ends of the oocyte. Tsl protein has been shown to be specifically localized to the polar regions of the VM in laid eggs. Although Tsl can associate with nonpolar regions of the VM, the activity of polar-localized Tsl is enhanced, suggesting the existence of another spatially restricted factor acting in this pathway. The incorporation of Tsl into the VM provides a mechanism for the transfer of spatial information from the follicle cells to the developing embryo. Tsl represents the first example of an embryonic patterning determinant that is a component of the eggshell (Stevens, 2003).
Activation of Tsl may be spatially regulated through the action of gap genes. Spatial regulation of the expression of the gap genes, the first zygotic patterning genes to be expressed during embryogenesis, is determined by the activity of the three maternal pathways (anterior, posterior, and terminal) required for the development of the anterior-posterior axis of the embryo. In addition to localized maternal input, interactions between the gap gene products themselves led to further refinement of their expression domains. tll expression, for example, is specifically repressed in the segmented region of the embryo by central gap gene products such as Kr. Thus, depending on their relative levels of activity, Kr and Tll are both capable of suppressing one another's expression. This raises the possibility that centrally expressed Kr is responsible for the polar restriction of tll expression that is observed in the progeny of tsl mutant females expressing tsl from the germline. To address this question, the CBBtsl insertion was crossed into females that were mutant for all three anterior-posterior maternal pathways. Embryos produced by mothers triply mutant for bicoid (anterior), oskar (posterior), and tsl (terminal) lack all anterior-posterior patterning, express low levels of Kr uniformly along the anterior-posterior axis, and do not express tll at all. In contrast, the embryos produced by triply mutant females carrying CBBtsl did express tll in distinct polar domains, either at the anterior alone or at both poles. Consistent with this pattern of tll expression, Kr expression is specifically repressed in the corresponding polar domains. Further, these embryos also differentiate Filzkörper material, a posterior cuticular structure that requires terminal pathway activity, at one or both poles. Thus, although Tsl was distributed uniformly in their VMs, these embryos developed gap gene expression patterns and cuticular phenotypes consistent with polar activation of the Tor receptor. These findings suggest that the activity of Tsl is enhanced at, and perhaps restricted to, the polar regions of the VM; this finding implies that there is an as yet unidentified component of the terminal class pathway that is restricted to the poles and is required for the function of Tsl (Stevens, 2003).
The existence of another localized factor in this pathway indicates that there are at least four levels of control that ensure the polar restriction of tll expression during embryonic development. (1) First to act is the restriction of tsl expression to a specific subpopulation of follicle cells present at the poles of the oocyte. (2) Next is the stabilization of secreted Tsl protein at the poles of the VM and its incorporation into the eggshell in an active form. (3)The facilitation of Tsl function follows, through its proposed interaction with another localized factor. (4)The final layer of control is the exclusion of tll expression from nonpolar regions through the inhibitory effects of centrally expressed gap genes. Although it has long been assumed that the spatial restriction of tsl expression was the uniquely localized element in the terminal pathway, data is presented implying the existence of another factor that enhances the activity of Tsl specifically at the poles. The function of Tsl itself is unknown, and there are currently no candidate genes encoding proteins with the enzymatic activity to bring about the proposed processing of the Trk precursor. It is likely, therefore, that the identification of this factor will greatly enhance understanding of the mechanism by which the Tor ligand is formed (Stevens, 2003).
Drosophila segmentation is governed by a well-defined gene regulation network. The evolution of this network was investigated by examining the expression profiles of a complete set of segmentation genes in the early embryos of the mosquito, Anopheles gambiae. There are numerous differences in the expression profiles as compared with Drosophila. The germline determinant Oskar is expressed in both the anterior and posterior poles of Anopheles embryos but is strictly localized within the posterior plasm of Drosophila. The gap genes hunchback and giant display inverted patterns of expression in posterior regions of Anopheles embryos, while tailless exhibits an expanded pattern as compared with Drosophila. These observations suggest that the segmentation network has undergone considerable evolutionary change in the dipterans and that similar patterns of pair-rule gene expression can be obtained with different combinations of gap repressors. The evolution of separate stripe enhancers in the eve loci of different dipterans is discussed (Goltsev, 2004).
In Drosophila, different levels of the Hunchback and Knirps gap repressor gradients define the limits of eve stripes 3, 4, 6, and 7, while Giant and Kruppel establish the borders of stripes 2 and 5. In situ hybridization probes were prepared for Anopheles orthologues of all four of these gap genes, as well as a fifth gap gene, tailless. hunchback displays a broad band of expression in the anterior half of the Anopheles embryo, encompassing both the presumptive head and thorax. This pattern is similar to that observed in Drosophila, although there are a few notable deviations: (1) there is no obvious maternal expression seen in early Anopheles embryos, whereas maternal hunchback mRNAs are strongly expressed throughout early Drosophila embryos; (2) there is a significant change in the posterior staining pattern. The Drosophila gene displays a strong posterior stripe of expression that is comparable in intensity to the anterior staining pattern. In Anopheles, this staining is significantly weaker than that of the anterior domain, and the posterior pattern is shifted anteriorly into the presumptive abdomen (Goltsev, 2004).
The Kruppel and knirps staining patterns are similar in Anopheles and Drosophila embryos. In both cases, the principal sites of expression are seen in the presumptive thorax and abdomen, respectively. However, the remaining two gap genes, giant and tailless, exhibit distinctive staining patterns. In Anopheles, giant exhibits a continuous band of staining in anterior regions, whereas the Drosophila gene is excluded from the anterior pole. Moreover, there is a prominent band of staining in the presumptive abdomen of Drosophila embryos that is not seen in Anopheles. Finally, tailless is expressed in a narrow stripe in the posterior pole of Drosophila embryos, whereas Anopheles embryos display a dynamic pattern that (transiently) extends throughout the presumptive abdomen (Goltsev, 2004).
The altered patterns of hunchback and giant expression in posterior regions raise the possibility that different combinations of gap repressors are used to establish eve stripes 5, 6, and 7 in Anopheles and Drosophila. It is unlikely that Giant establishes the posterior border of eve stripe 5 and that Hunchback delimits the posterior border of stripe 7, as seen in Drosophila. The expression profiles of additional gap genes were analyzed in an effort to identify potential repressors for these stripe borders. The most obvious candidates are huckebein and tailless, since both are expressed in the posterior pole of Drosophila embryos. No expression of huckebein was seen in early embryos, although strong staining appears after germband elongation (Goltsev, 2004).
The gap gene tailless is initially detected at the anterior and posterior poles, with roughly equivalent levels of staining at the two sites. At slightly later stages, the anterior domain is lost, and the posterior pattern expands throughout the presumptive abdomen. The tailless transcripts detected in posterior regions exhibit a graded distribution, with peak levels at the posterior pole and progressively lower levels in more anterior regions. During cellularization, staining is reduced in posterior regions and reappears near the anterior pole. This broad and dynamic staining pattern is consistent with the possibility that the Tailless repressor specifies the posterior borders of one or more posterior eve stripes (Goltsev, 2004).
Torso signaling was examined in the Anopheles embryo in an effort to understand the basis for the expanded tailless expression pattern. In Drosophila, tailless is activated by the Torso signaling pathway, which can be visualized with an antibody against diphospho (dp)-ERK. The antibody detects localized staining in the terminal regions of early Drosophila embryos. A similar staining pattern is detected in Anopheles, although staining may be somewhat broader in Anopheles than Drosophila. It is therefore conceivable that the expansion of the posterior tailless expression pattern seen in Anopheles might be due to an expanded activation of the Torso signaling pathway (Goltsev, 2004).
In Drosophila, eve stripes 6 and 7 are regulated by different concentrations of Knirps and Hunchback. Low levels of Knirps define the anterior border of stripe 7, while higher levels are needed to repress eve stripe 6. Conversely, low levels of Hunchback establish the posterior border of eve stripe 6, while higher levels regulate stripe 7. The position of the knirps expression pattern is consistent with the possibility that it defines the anterior limits of stripes 6 and 7, just as in Drosophila. However, the posterior borders of these stripes are probably not regulated by Hunchback. The expanded pattern of tailless expression seen in Anopheles might permit it to establish the posterior border of eve stripe 6 and possibly stripe 7. An alternative candidate for the posterior stripe 7 border is giant, which is expressed in a tight domain within the posterior pole. Consistent with this possibility is the observation that the posterior giant pattern comes on relatively late, and the posterior stripe 7 border is the last to form among the seven eve stripes. The reversal of the posterior hunchback and giant expression patterns, along with the expanded tailless pattern, strongly suggests that different combinations of gap repressors are used to define eve stripes 5, 6, and 7 in Drosophila and Anopheles (Goltsev, 2004).
The intrinsic neurons of mushroom bodies (MBs), centers of olfactory learning in the Drosophila brain, are generated by a specific set of neuroblasts (Nbs) that are born in the embryonic stage and exhibit uninterrupted proliferation till the end of the pupal stage. Whereas MB provides a unique model to study proliferation of neural progenitors, the underlying mechanism that controls persistent activity of MB-Nbs is poorly understood. This study shows that Tailless (Tll), a conserved orphan nuclear receptor, is required for optimum proliferation activity and prolonged maintenance of MB-Nbs and ganglion mother cells (GMCs). Mutations of tll progressively impair cell cycle in MB-Nbs and cause premature loss of MB-Nbs in the early pupal stage. Tll is also expressed in MB-GMCs to prevent apoptosis and promote cell cycling. In addition, it was shown that ectopic expression of tll leads to brain tumors, in which Prospero, a key regulator of progenitor proliferation and differentiation, is suppressed whereas localization of molecular components involved in asymmetric Nb division is unaffected. These results as a whole uncover a distinct regulatory mechanism of self-renewal and differentiation of the MB progenitors that is different from the mechanisms found in other progenitors (Kurusu, 2009).
tll was expressed in the dividing MB-Nbs and GMCs, but not in the postmitotic neurons, through the stages of MB development. Tll expression is initially found in almost all procephalic neuroblasts, but became largely restricted to anterior cells by stage 16. Double immunostaining with an anti-Dac antibody, which labels MB neurons, confirmed that they were MB-Nbs and GMCs. In the larval stages, Tll is expressed in the MB-Nbs and GMCs as well as in lamina precursor cells. While the expression in lamina precursor cells disappears by the end of the larval stage, Tll expression in the MB progenitors is maintained during the pupal stages. In newly eclosed flies, Tll expression was found in a few GMC-like cells in the middle of the MB cell clusters, although their exact identity is unknown (Kurusu, 2009).
Several lines of evidence indicate that Tll is cell autonomously required for efficient proliferation activity MB-Nbs. BrdU labeling experiments
demonstrate that DNA synthesis is partially suppressed in tll mutant Nbs in both the larval and the pupal stages. Cell cycle defects in the mutant MB-Nbs are not evident in the larval stage but confirmed by marked suppression of PH3 and Cyc B activity at 20 h APF before the disappearance of mutant Nbs. As a whole, these data suggest that Tll is required to maintain efficient
cell cycle progression in MB-Nbs, particularly in the pupal stage. In contrast, although the premature loss of the mutant Nbs might be a consequence of cell cycle exit as has been suggested with other Nbs,
the exact mechanism of the disappearance of mutant MB-Nbs in the early
pupal stage is unknown. It is also plausible that mutant Nbs are
removed by apoptosis, as is the case with mutant GMCs, although TUNEL signals for MB-Nbs were not detected at 20 h APF, shortly
before their disappearance whereas cell death signals in GMCs are
evident at both the larval and pupal stages (Kurusu, 2009).
Despite marginal reduction in cell division activity of MB-Nbs at the larval stage, loss of tll activity results in significant reduction of the larval MB clones. Instead, the results demonstrate that cell cycle progression is impaired in larval MB-GMCs. Moreover, the majority of the MB-GMCs are lost by cell death. The molecular mechanism underlying these GMC defects is yet to be investigated, but it is unlikely that they are mediated by altered Pros
expression since Pros is co-expressed with Tll in wild-type MB-GMCs, and its expression is unaltered in mutant GMCs. In addition, the results demonstrating that neither p35 nor Diap1 rescues GMC death suggest that Tll might be involved in suppression of an unconventional cell death pathway (Kurusu, 2009).
What is the molecular function of Tll in the regulation of MB progenitors?
The fact that Tll is a transcription factor localized in the nucleus
suggests that Tll might specify neuronal identity of MB progenitors by
regulating cell-type specific genes. However, unlike other regulatory
factors that confer either spatial or temporal identity, Tll is
expressed only in Nbs and GMCs, and mutant neurons exhibit wild-type
like dendritic and axonal wiring patterns even in the adult stage, in which perdurance of wild-type tll activity in the mutant clones is unlikely. Rather, Tll might provide MB progenitors with cellular identity that specify a distinctive proliferation pattern, either by promoting cell cycle or by preventing apoptosis or by both in parallel. In any case, such identity cannot be determined by Tll on its own because Tll is expressed in other neuronal
progenitors such as lamina precursor cells in the optic lobes.
Instead, it is presumed that the proliferation identity of MB progenitors
may be specified in combination with other regulatory factors such as
Eyeless, which is expressed in MB-Nbs, GMCs and postmitotic neurons to
control MB development (Kurusu, 2009).
In the course of MB proliferation, Tll might downregulate key regulatory
genes involved in cell-cycle exit and differentiation, particularly
given the fact that Tll functions mostly as a repressor in the early
embryogenesis. One such candidate gene is pros. Pros is detected in MB-GMCs, but not MB-Nbs. However, loss of pros causes neither tumorous transformation of MB progenitors nor suppression of tll phenotype in pros tll double mutant clones. Moreover, Pros is not upregulated in tll mutant clones. Thus, these data argue against the involvement of pros in the regulation of MB progenitors although they do not exclude a
redundant mechanism involving Pros cooperating with other factors.
Alternatively, Tll could indirectly control cell cycle progression by
downregulating genes that suppress progenitor division. In support of
this, it is noteworthy that the mammalian homolog Tlx (NR2E1) represses a tumor suppressor gene, Pten, via consensus Tll/TLX binding sites located in the pten promoter, and thereby indirectly stimulates the expression of various cell cycle genes including Cyclin D1, p57 kip2, and p27 kip1 (Kurusu, 2009).
Studies on Drosophila neural progenitors reveal heterogeneity among the brain Nbs in terms of temporal windows of cell division, patterns of self-renewal, and susceptibility to mutations that regulate proliferation and termination of progenitors. Among the Nbs in the Drosophila
brain, MB-Nbs exhibit a highly unique proliferation pattern. Most Nbs
pause cell division between the late embryonic and the early first instar stages, and cease proliferation by the early pupal stage. By contrast, MB-Nbs divide continuously from the embryonic stage till the end of pupal stage, generating diverse identities of neurons by temporal order. In house cricket and moth, proliferation activity of MB-Nbs further extends beyond the pupal stage to exhibit persistent neurogenesis during adult life (Kurusu, 2009).
Although the data clearly indicate a pivotal function of Tll for persistent
proliferation and maintenance of MB-Nbs, the mechanism that determines
the exit from cell cycling at the end of pupal stage remains elusive.
Neither extension of Tll expression beyond the end of the pupal period
nor blocking cell death program, by p35 or Diap1, prolonged MB-Nb
proliferation beyond the pupal stage, suggesting existence of other mechanisms that schedule the end of MB-Nb activity. In most brain Nbs, a burst of Pros in the nucleus at around 120 h after larval hatching (24 h APF) induces cell cycle exit to regulate generation of postmitotic progeny in the brain.
However, no burst of nuclear Pros is detected for MB-Nbs at the end of
the pupal stage when they finally exit from cell cycling,
although the data demonstrate that, as is the case with other Nbs in
the brain, Pros indeed has such regulatory potential in larval MBs that
its overexpression results in partial loss of the MB-Nbs. Moreover, MB clones lacking pros activity, which exhibit normal growth, cease cell division by the end of the pupal stage (Kurusu, 2009).
During asymmetric cell division of Drosophila Nbs, Pros is kept inactive by tethering to the cell cortex by MIRA.
At telophase of Nb cell cycle, Pros is segregated into GMC, where it
enters the nucleus to trigger cell cycle exit and promote
differentiation of post mitotic progeny that are generated by the
division of GMC. Accordingly, nuclear Pros is expressed at high levels
in postmitotic neurons and at moderate levels in GMCs. However, whereas this partition pattern of Pros in the post-embryonic brain is shared between MB and non-MB progenies, Pros seems dispensable for cell-cycle control of MB-GMCs. In non-MB lineages, loss of pros activity in GMCs leads to failure of cell-cycle exit and transforms of GMCs into Nbs. However, loss of pros activity never causes transformation of MB-GMCs although mutant MB neurons exhibit considerable dendritic defects. In contrast, Tll is expressed
and required for MB-GMCs to suppress apoptosis and maintain active cell
cycling. Intriguingly, whereas Pros is suppressed by Tll in non-MB
progenitors, both proteins are coexpressed in MB-GMCs, clearly suggesting that, as compared to the progenitors of non-MB lineages, a different mechanism may operate in MB progenitors to control the expression of regulatory factors that are important for cell division and differentiation (Kurusu, 2009).
The brain hyperplasia produced by Tll overexpression is reminiscent of
brain tumors caused by mislocalization of asymmetric determinants.
Aberrant Nb divisions that disrupt the positioning of such factors
generate brain tumors. Brain tissues from pins, mira, numb, or pros mutants generate tumors when transplanted in the wild-type abdomen. In double mutants of pins and lgl,
mislocalization of aPKC in the basal cortex results in the generation
of supernumerary Nbs at the expense of GMCs, and thus, neurons.
BRAT is required for the asymmetric positioning of Pros, which in turn
suppresses self-renewal of GMC and promotes cell differentiation by
transcriptional control. Mutant clones of either brat or pros are highly tumorigenic, forming a large number of MIRA-positive Nbs (Kurusu, 2009).
While recapitulating the tumor phenotype, ectopic expression of Tll does not
affect asymmetric localization of aPKC, PINS, and BRAT. Instead, Tll downregulates Pros in hyperplasic brains and in overexpression clones, suggesting that the tumorigenesis phenotype caused by Tll
expression is mediated by Pros downregulation in GMCs. This notion is
further supported by the fact that coexpression of Pros with Tll
suppresses brain hyperplasia. Notably, the cis-regulatory region of pros harbors a consensus Tll binding site within 500 base pairs from the
transcriptional initiation site, consistent with the idea that Tll might repress transcription of pros via direct DNA binding (Kurusu, 2009).
Recently, atypical large Nb lineages in the dorsomedial part of the larval brain have been described and designated as Posterior Asense-Negative (PAN)
Nbs. Nbs of such lineages divide asymmetrically to self renew, but, unlike
other Nbs, generate smaller intermediate progenitors that express Nb
markers. The fact that these atypical Nbs are MIRA-positive and Pros
negative raises a possibility that tumor clones induced by Tll could
either correspond to or originate from them. As with other Nbs, clones
of the PAN-Nb lineages accompany only a single large Nb, with their
progeny arranged regularly in a columnar order. By contrast, clones generated by Tll overexpression harbor several large to intermediate-sized Nbs, exhibiting irregular morphology, which is typical of tumors. PAN-Nbs are the Nb subpopulation that exhibits overgrowth in brat mutants. However, it is also unlikely that Tll induced overgrowth originates from overgrowth of PAN Nbs, which correspond to eight Nbs in the DPM group among the ~90 Nbs per hemisphere. On the contrary, Tll induces clonal tumors not only in DPM but also in CM and BLP lineages. Indeed, Tll overgrowth phenotype is not localized to a specific location of the hemisphere, but broadly detectable in the brain
including the optic lobe. Moreover, Tll overgrowth phenotype is also induced in the embryonic CNS, arguing against the involvement of larval PAN-Nbs (Kurusu, 2009).
The Drosophila Tll and the vertebrate homolog TLX (NR2E1) share high sequence similarity in the DNA binding domain. Tlx mutant mice exhibit a reduction of rhinencephalon and limbic structures with emotional and learning defects. Notably, Tlx mutant mice exhibit reduction of neuron numbers in cortical upper layers. Postnatally, TLX is localized to the adult neurogenic regions including the subgranular layer of the dentate gyrus to maintain stem cells in a proliferative and undifferentiated state.
Recent behavioral studies have shown that such TLX-positive neural stem
cells actually contribute to animal's spatial learning. Thus, combined with the current results, these studies highlight a functional commonality of the tll/Tlx homologs between flies and mammals, and imply an intriguing evolutionary conservation of the genetic programs underlying neural
progenitor controls in crucial brain structures involved in memory and
other cognitive functions (Kurusu, 2009).
Intriguingly, the mammalian pros homolog Prox1 promotes cell cycle exit and differentiation of the neural progenitors in the developing subventricular zone and the retina, the neural tissues in which Tlx functions antagonistically to control progenitor proliferation. Based on the tll GOF phenotypes in Drosophila, it is predicted that deregulation of Tlx in the developing brain may cause suppression of Prox1 and could result in severe neurological tumors in humans. On the other hand, consistent with the loss-of-function phenotypes in flies, several
mutations have been identified in the regulatory regions of Tlx in humans with microcephary. Given the commonality in progenitor control, further studies of the Drosophila MB-Nbs may shed light on the molecular basis of the proliferation and differentiation of neural progenitors, and would provide important cues for understanding progenitor disorders in the human brain (Kurusu, 2009).
tailless mutants exhibit deletions in the terminal (anterior and posterior) domains of the embryo. There is a correlation between the presence of the posterior cap of tll expression and differentiation of a telson. In the anterior the maternal anterior system, Bicoid is required together with the terminal system and its target tailless to establish the acron (Pignoli, 1992). tailless is responsible in the tail for hindgut and Malpighian tubules and a large portion of the posterior midgut, hindgut and anal pads.
In mutants of huckebein and tailless, genes known to specify, respectively, adjacent posterior and anterior domains of the posterior midgut invagination, folded gastrulation transcription at the posterior pole does not extend as far anteriorly. The same lack of extention is evident in forkhead mutants. The double mutant huckebein tailless is the only double mutant combination of these three genes that completely eliminates the posterior midgut invagination; this combination also abolishes all expression of fog at the posterior pole. It is not clear how the anterior extent of fog transcription is delimited, since the domain of tailless expression and activity extends further to the anterior than the region of fog expression (Costa, 1994).
tailless mutations have little effect on hindsight expression; from analysis of huckebein tailless double mutants, it is clear that the only loss of Hnt protein expression in tailless mutants occurs in the region from which the Malpighian tubule primordia originate, consistent with the reported role for tll and hnt in the development of these structures. hkb mutant embryos lack Hnt protein expression in the regions from which the anterior and posterior midgut normally arise; expression remains only in the presumptive ureter of the Malpighian tubules. In hkb tll double mutant embryos, Hnt protein is not present at all in the domains that would form anterior and posterior midgut and Malpighian tubule primordia; however expression does occur in the amnioserosa. Germ-band retraction occurs in tll or hkb single mutants as well as in hkb tll double mutants, suggesting that midgut expression of Hnt is not necessary for germ-band retraction (Yip, 1997).
Mammalian cell culture studies have shown that several members of the nuclear receptor super family such as glucocorticoid receptor, retinoic acid receptor and
thyroid hormone receptor can repress the activity of AP-1 proteins (referring to Drosophila Kayak and Jun) by a mechanism that does not require the nuclear receptor to bind to DNA directly, but that is
otherwise poorly understood. Several aspects of nuclear receptor function are believed to rely on this inhibitory mechanism, which is referred to as transrepression.
This study presents evidence that nuclear receptor-mediated transrepression of AP-1 occurs in Drosophila melanogaster. In two different developmental situations,
embryonic dorsal closure and wing development, several nuclear receptors, including Seven up, Tailless, and Eagle antagonize AP-1. The inhibitory interactions with
nuclear receptors are integrated with other modes of AP-1 regulation, such as mitogen-activated protein kinase signaling. A potential role of nuclear receptors in
setting a threshold of AP-1 activity required for the manifestation of a cellular response is discussed (Gritzan, 2002).
The best understood AP-1-dependent process in Drosophila development is a coordinated cell sheet movement known as dorsal closure. During DC, lateral epidermal cells migrate dorsally and close the epidermis on the dorsal side of the embryo. Failure to undergo DC results in a characteristic dorsal open phenotype, the cuticle of affected embryos displays a dorsal hole. Mutations in genes encoding the Drosophila homologs of JNKK, (JNK, Jun and Fos) all give rise to similar dorsal open phenotypes. Thus, it is thought that DC requires activation of Jun/Fos heterodimers by a JNK-type MAPK cascade. Embryos homozygous for kay1, a fos null allele are devoid of zygotic Fos activity and DC fails. A large dorsal hole forms and the cuticle collapses. In an embryo homozygous kay2, a hypomorphic fos-allele, AP-1 activity is reduced but not eliminated. Correspondingly, the DC phenotype is weaker. The embryo displays a small dorso-anterior hole (Gritzan, 2002).
To test whether Drosophila NRs can antagonize AP-1, a variety of AP-1 constructs were in the embryonic epidermis. Interestingly, expression of some, but not all, NRs tested result in DC phenotypes of different strengths. Expression of Svp in the dorsal epidermis under the control of pnrGal4 results in a DC phenotype reminiscent of that of kay2 homozygotes. This finding is consistent with a suppression of AP-1 activity by Svp. Similarly, expression of Tll under the control of a heat shock promoter causes a weak dorsal open phenotype. The differentiation of ventral cells does not seem to be disturbed by Tll expression since the pattern of denticles in this part of the epidermis appears grossly normal. Thus, Tll expression specifically affects the dorsal epidermis where AP-1 activity is required. The expression of Knrl under the control of pnrGal4 elicits stronger DC phenotypes with the dorsal hole frequently extending over several segments (Gritzan, 2002).
Does modulation of AP-1 activity by NRs occur only in situations where AP-1 is regulated by JNK or does this type of regulation also operate in different contexts? A function for Fos downstream of ERK has been demonstrated in the differentiation of wing veins. Extra vein material can result from elevated levels of ERK, as in flies carrying a gain-of-function allele of the rolled gene, which encodes Drosophila ERK. This allele, called rolledSevenmaker (rlSem), encodes a form of ERK with increased resistance to inactivation by dephosphorylation. Expression of a dominant-negative form of Fos in the wings of rlSem flies results in loss of ectopic vein material. Conversely, overexpression of Fos enhances the extra-vein phenotype caused by rlSem. 32B Gal4, UAS Sem flies express the RlSem form of ERK in the wing from a UAS-driven transgene. As a consequence of elevated levels of ERK activity, these animals develop ectopic wing vein material. Reducing fos gene dosage in this system strongly suppresses the vein phenotype, consistent with the proposed role of Fos as an ERK effector. Thus, 32B Gal4 UAS Sem flies provide a suitable system to examine how genetic manipulations of AP-1 activity affect vein differentiation. To investigate a potential role of the Drosophila NRs in this process, one copy of kni, eg, tll or svp was removed in 32B Gal4, UAS Sem flies. Reducing kni function does not influence the vein phenotype. However, heterozygosity for any of the other three receptors tested reproducibly leads to a mild enhancement of the ectopic vein differentiation. As an unambiguously scoreable criterion to statistically evaluate phenotypic effects, the presence of ectopic vein material posterior to L5 was chosen. This area of the wing is relatively resistant to the formation of extra vein material. Quantitative analysis clearly shows that whereas the formation of extra vein material posterior to L5 in 32B Gal4 UAS Sem flies is suppressed by reducing fos activity, it is enhanced by a reduction of eg, svp or tll function. These data suggest that all three NRs antagonize AP-1 activity in wing vein differentiation, conceivably in a redundant manner (Gritzan, 2002).
It is speculated that the modulation of AP-1 activity by NRs contributes to what has recently been termed signal consolidation. Cells have to place a value on incoming signals (e.g. EGF-induced ERK activity) such that they are either answered by a biological response (e.g. the execution of a transcriptional program) or disregarded as noise. It is proposed that the modulation of AP-1 activity by NRs facilitates the interpretation of the EGF signal in wing vein differentiation by defining a threshold of ERK activity. Cells in which ERK activity does not reach this threshold do not mount an AP-1-dependent transcriptional response to the EGF signal. When transrepressional control is impaired (as in the svp, tll double mutant clones) the threshold is lowered and more cells than appropriate interpret EGF-induced ERK activity as a consolidated signal. This leads to the formation of ectopic vein material. This model is supported by the finding that the ectopic vein tissue observed in clones of tll and svp mutant tissue did arise close to the position of the endogenous veins and not randomly throughout the clonal area. Thus, the regulation of AP-1 by NRs appears to convey cell-intrinsic information (Gritzan, 2002).
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tailless:
Biological Overview
| Evolutionary Homologs
| Regulation
| Targets of Activity
| Developmental Biology
| Effects of Mutation
date revised: 10 November 2010
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