Interactive Fly, Drosophila




Expression of hkb is first detected in the terminal regions (anterior and posterior) of the syncytial blastoderm. With the beginning of gastrulation, the anterior cap moves ventally so that the invaginating ventral furrow [Image] is tightly framed by hkb expression. Later hkb expression is confined to the placodes of the salivary glands and to a metameric pattern in the developing central nervous system (Bronner, 1994).

See Chris Doe's Hyper-Neuroblast map site for information on the expression of huckebein in specific neuroblasts.

The mechanisms leading to the specification and differentiation of ventral nerve cord neuroblast lineages in Drosophila are largely unknown. Mechanisms that lead to cell differentiation within the NB 7-3 lineage have been analyzed. Analogous to the grasshopper, NB 7-3 is the progenitor of the Drosophila serotonergic neurons. The zinc finger protein Eagle (Eg) is expressed in NB 7-3 just after delamination and is present in all NB 7-3 progeny until late stage 17. eagle is required for normal pathfinding of interneuronal projections and for restricting the cell number in the thoracic NB 7-3 lineage. eg is required for serotonin expression. Ectopic expression of Eg protein forces specific additional CNS cells to enter the serotonergic differentiation pathway. Like NB 7-3, the progenitor(s) of these ectopic cells express Huckebein (Hkb), another zinc finger protein. However, and in contrast to the NB 7-3 lineage, where engrailed acts upstream of eg, the ectopic progeny do not express engrailed. It is concluded that eg and hkb act in concert to determine serotonergic cell fate, while en is more distantly involved in this process by activating eg expression. This is the first functional evidence for a combinatorial code of transcription factors acting early but downstream of segment polarity genes to specify a unique neuronal cell fate (Dittrich, 1997).

Defects in single minded mutants are characterized by the loss of the gene expression required for the proper formation of the ventral neurons and epidermis, and by a decrease in the spacing of longitudinal and commissural axon tracks. Molecular and cellular mechanisms for these defects were analyzed to elucidate the precise role of the CNS midline cells in proper patterning of the ventral neuroectoderm during embryonic neurogenesis. These analyses have shown that the ventral neuroectoderm in the sim mutant fails to carry out its proper formation and characteristic cell division cycle. This results in the loss of the dividing neuroectodermal cells that are located ventral to the CNS midline. The CNS midline cells are also required for the cell cycle-independent expression of the neural and epidermal markers. This indicates that the CNS midline cells are essential for the establishment and maintenance of the ventral epidermal and neuronal cell lineage by cell-cell interaction. Nevertheless, the CNS midline cells do not cause extensive cell death in the ventral neuroectoderm. This study indicates that the CNS midline cells play important roles in the coordination of the proper cell cycle progression and the correct identity determination of the adjacent ventral neuroectoderm along the dorsoventral axis (Chang, 2000).

The hkb gene is a useful marker for NBs delaminating at the S2-S5 stages of neurogenesis. hkb, expressed in the broad area of the ventral neuroectoderm, was used to determine whether the CNS midline cells affect the formation and identity determination of many NBs delaminating at later S2-S5 stages after the initial round of neurogenesis has begun. The hkb expression starts in the neuroectoderm of medial NB 2-2 and intermediate NB 4-2 at the middle of stage 9. At stage 10, hkb is expressed in the S3 NBs 2-2 and 4-2 and in the neuroectodermal clusters of NBs 2-4, 4-4, and 5-4 and finally in the S5 NBs 2-1, 2-2, 2-4, 4-2, 4-3, 4-4, 5-4, 5-5, and 7-3 at late stage 11. In sim embryos at stage 10, hkb expression in NBs 2-2 and 4-2 and in the neuroectodermal clusters of NBs 2-4, 4-4, and 5-4 is absent in 94% of hemisegments in sim embryos (Chang, 2000).

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).

huckebein (hkb), a terminal gap gene, is first expressed at the anterior and posterior blastodermal poles, where it is required for the specification of the endodermal anlagen, and later for the invagination of the stomodeum. After gastrulation, hkb becomes transiently expressed in a repetitive pattern in the trunk neuroectoderm and in eight, mainly intermediate, NBs per hemineuromere. In the procephalic region at the cellular blastoderm stage, hkb (Urbach, 2003).

Expression is detected in a centrally located stripe and a dorsal ectodermal spot. hkb in situ hybridization combined with anti-Inv antibody staining reveals that during stage 9/10 the hkb stripe covers most of the antennal ectoderm and reaches into the anterior region of the intercalary segment, and the hkb spot covers part of the ocular ectoderm. During stage 9 hkb transcript in the ocular spot becomes progressively restricted to the delaminating protocerebral NBs, Pcv7 and Pcd2, and remains strongly expressed in both NBs until stage 11. In the antennal domain during stage 10/11 the transcript becomes confined to three to five deutocerebral NBs. However, using a hkb-lacZ line (5953) the marker is expressed in all deutocerebral NBs at stage 10. At stage 11, hkb-lacZ was not detectable in Dd8 and Dd11, indicating that hkb is not a general deutocerebral NB marker. In the tritocerebrum, hkb is expressed only in Td6 (stage 10) and in Tv1, Td8. Thus, although expressed in a few trito- and protocerebral NBs, hkb expression appears to be mainly confined to the antennal neuroectoderm and NBs. Compared with the transcript, which becomes restricted to the NBs during stage 9-11, hkb-lacZ expression has a longer perdurance in the peripheral ectoderm and corresponding NBs. By stage 14, most of the hkb transcript has disappeared and is confined to some deutocerebral cells; hkb-lacZ is strongly expressed until the end of embryogenesis in deutocerebral, and at a lower level, in protocerebral cells, the putative progeny of the identified Hkb-positive brain NBs (Urbach, 2003).

Effects of Mutation or Deletion

huckebein is required for germ-layer formation in the blastoderm. Absence of the hkb product causes the ectodermal and mesodermal primordia to expand at the expense of endoderm anlagen. Conversely, ectopic expression of hkb inhibits the formation of the major gastrulation fold which gives rise to the mesoderm and prevents normal segmentation in the ectoderm. Thus, hkb is necessary for endoderm development and its activity defines spatial limits within the blastoderm embryo in which the germ layers are established. Another consequence of mutation is the trapping of germ cells in the ectodermal hindgut. Under normal conditions, they would migrate through the endodermal midgut into the gonadal mesoderm (Bronner, 1994).

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).

huckebein encodes a predicted zinc finger transcription factor that is transiently expressed in a subset of Drosophila central nervous system precursors [neuroblasts (NBs)]. Cell lineage tracing and cell fate markers were used to investigate the role of huckebein in the NB 1-1 and NB 2-2 cell lineages. Loss of huckebein does not switch these NBs into different NB fates, nor does it change the number of cells in their lineages; rather, it is required for glial development in the NB 1-1 lineage, and for axon pathfinding of a subset of interneurons and motoneurons in both lineages (Bossing, 1996).

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).

During Drosophila development, the salivary primordia are internalized to form the salivary gland tubes. By analyzing immuno-stained histological sections and scanning electron micrographs of multiple stages of salivary gland development, it has been showm that internalization occurs in a defined series of steps, involves coordinated cell shape changes, and begins with the dorsal-posterior cells of the primordia. The ordered pattern of internalization is critical for the final shape of the salivary gland. In embryos mutant for either huckebein (hkb), which encodes a transcription factor, or faint sausage (fas), which encodes a cell adhesion molecule, internalization begins in the center of the primordia, and completely aberrant tubes are formed. The sequential expression of hkb in selected cells of the primordia presages the sequence of cell movements. It is proposed that hkb dictates the initial site of internalization, the order in which invagination progresses and, consequently, the final shape of the organ. It is proposed that fas is required for hkb-dependent signaling events that coordinate internalization (Myat, 2000).

During embryogenesis, cells of the salivary gland primordia, which initially reside at the ventral surface, are internalized to form the tubular salivary glands in less than 4 hours. To analyze gross morphology during internalization, wild-type (WT) embryos were stained with antisera to dCREB-A, a transcription factor expressed to high levels in the nuclei of salivary gland secretory cells, and whole-mount embryos were examined. From this analysis, four distinct stages of salivary gland internalization can be described. During stage I, the salivary gland secretory cell primordia forms the two salivary gland placodes at the ventral surface of the embryo. During stage II, an invaginating pit forms in the dorsal-posterior region of each placode, about one to two rows of cells from the dorsal-posterior edge. During stage III, a non-uniform tube is observed with a narrow distal portion, which forms from the dorsal-posterior cells that internalize first, and a bulbous proximal portion, which forms when both dorsal-medial and dorsal-anterior cells are internalized. As the remaining ventral cells of the placode invaginate during stage IV, a more uniformly sized, bent tubular organ is formed. The distal portion of the tube is directed posteriorly and the proximal portion of the tube is directed approximately dorsally. Salivary gland secretory cell internalization is complete when the last ring of cells invaginates. Once the duct cells have internalized, the secretory portion of the gland is 'cigar-shaped', and is directed posteriorly, extending to the level of the third thoracic segment and dorsolateral to the ventral nerve cord (Myat, 2000).

Histological analyses of salivary glands at the four stages described above have been carried out to analyze changes in cell shape during internalization. During stage I, when the salivary gland placode cells are at the ventral surface, they are elongated, and their nuclei are distributed randomly between the apical and basal portions of the cells, and cell morphology is uniform throughout the primordia. During stage II, cells in the dorsal-posterior region of the placode are wedge-shaped and have invaginated to form a small pit. The apical surface membranes of the dorsal-posterior cells are constricted and their nuclei are uniformly localized to a basal domain within each cell. In contrast, 2-3 rows of cells at the ventral-posterior edge of each primordia, and the remainder of cells in the placode do not change shape and appear as they did in stage I. One or two rows of cells at the dorsal-posterior edge of the primordia also remain anchored at the ventral surface, with no change in cell shape, apical membrane surface area or nuclear position. Sections through the salivary glands at stage III reveal a tube made up of a single layer of wedge-shaped cells surrounding a central lumen. During this stage, dorsal-medial cells have a characteristic wedge-shaped morphology with constricted apices and basal nuclei. The dorsal-anterior cells are becoming wedge-shaped; their nuclei have migrated basally, but their apical membrane is unconstricted. The ventralmost 2-3 rows of cells have not undergone any cell shape changes, and remain elongated with randomly located nuclei, like all placode cells at stage I. During stage IV of internalization, most of the secretory cells have invaginated into an elongated tube, with only a ring of cells remaining at the ventral surface. When this last ring of cells invaginates by changing shape, internalization of the secretory cells is complete. Although cells of the salivary gland tube remain wedge-shaped, they appear shorter than when they were at the embryo surface, suggesting that additional cell shape changes occur once cells are internalized. It is concluded that salivary gland internalization occurs through a wave of cell shape changes that begins with the dorsal-posterior cells. As dorsal-medial cells change shape and invaginate to follow the ingressing dorsal-posterior cells, the dorsal-anterior cells begin to change shape and invaginate. Next, the ventral-anterior and then the ventral-posterior cells change shape and invaginate. The last secretory cells to invaginate and internalize include the cells originally located at the dorsal-posterior edge of the placode. These data show that salivary gland internalization occurs, at least in part, through a mechanism driven by cell shape change, and suggest that the migration of nuclei to the basal domain and subsequent constriction of the apical surface membrane are prerequisites for cell shape change and invagination (Myat, 2000).

Among the earliest genes expressed in the salivary glands is huckebein (hkb), which encodes an Sp1/egr-like transcription factor. Whole-mount in situ hybridization to detect HKB mRNA in WT embryos and immuno-staining to detect beta-gal in a viable hkb P-element insertion line, AI7-hkb, reveal a dynamic expression pattern in the salivary gland primordia. At the stage when the salivary gland primordium is approximately square, hkb expression is first detected in a dorsal-posterior quadrant of approximately 4-5 rows of cells, correlating with the earliest expression of trachealess, dCREB-A and Sex combs reduced. Slightly later, when the salivary gland primordium becomes round-shaped, low levels of hkb expression are also observed in the dorsal-medial cells. hkb expression is excluded from the remaining cells of the placode at this stage. This pattern is soon followed by a second site of high level hkb expression in the dorsal-anterior cells of the placode. hkb expression levels in the ventral cells remain low. Just prior to internalization, low levels of HKB mRNA are observed in nearly all cells of the placode. HKB RNA is not detected once the dorsal-posterior cells have begun to internalize. The continued presence of beta-gal in the salivary gland during and after internalization, when the RNA for HKB is no longer detected, is probably due to the stability of beta-gal. Hkb protein expression in the salivary gland placode could not be assessed with the currently available anti-Hkb antibodies. This analysis demonstrates that the temporal expression of hkb in different regions of the placode presages the sequential wave of invagination that internalizes the secretory primordia. The dorsal-posterior cells are the first cells to express high levels of hkb, and are also the first cells to invaginate. Cells immediately anterior to the dorsal-posterior cells are the next group of cells to express hkb and are also the next to invaginate. The subsequent second site of high level hkb expression in the anteriormost region of the placode correlates with the cell shape changes observed in the anteriormost cells. Finally, low hkb levels are detected in almost all cells of the primordia just prior to the initiation of invagination (Myat, 2000).

Internalization and salivary gland shape are altered in hkbmutant embryos The dynamic pattern of hkb expression in the salivary gland placode suggests a possible role for hkb in directing internalization. Thus, salivary glands were examined in hkb mutants. By whole-mount analysis, the salivary gland placodes of hkb mutants look identical to those of WT embryos; the cells stain with anti-dCREB-A and reside at the ventral surface. The first defect observed at a gross morphological level is the incorrect positioning of the initial site of internalization: the first cells to internalize in hkb mutant embryos are those in the middle of the placode. Later, the salivary glands in hkb mutant embryos are trapezoidal-shaped in both ventral and lateral views. Although all of the secretory cells are internalized in hkb mutants, they never form the characteristic cigar-shaped tubes of the WT salivary glands; instead hkb mutants form dome-shaped structures that eventually fuse along the ventral midline. Thus, in addition to an early defect in the localization of the salivary gland pit, hkb mutant embryos form salivary glands whose shape is dramatically aberrant. The histological analysis of hkb mutant embryos supports the observations from the whole-mount analysis described above. When hkb mutant embryos are in stage I of salivary gland internalization, the placode cells look identical to WT placode cells; they are elongated with nuclei randomly positioned in the apical and basal domains. Later, the invaginated salivary gland pit of hkb mutant embryos is mislocated and is a mixture of wedge-shaped cells with constricted apices and basal nuclei, and elongated cells with randomly positioned nuclei. This arrangement of cell morphology in the hkb salivary gland pits is in contrast to that of WT embryos, where all cells that comprise the pit have approximately the same length, and are wedge-shaped with basal nuclei. The hkb pit is also wider and shallower than the WT salivary gland pits, and appears to include more cells. Although all secretory cells of hkb mutant embryos are eventually internalized, the salivary glands are positioned more anteriorly, and lie closer to the ventral midline and the body wall than the salivary glands of WT embryos. The two salivary glands of hkb mutant embryos then fuse at the ventral midline and form 'dome-shaped' organs with a common lumen. Dark Methylene Blue staining is detected in the lumen, which may correspond to salivary gland secretory products (Myat, 2000).

Salivary gland cells in embryos carrying a null allele of faint sausage (fas) do not invaginate. Examination of salivary gland morphogenesis in fas mutant embryos reveals that the cells invaginate but show gross morphological defects that are very similar to those of hkb mutant embryos. By whole-mount analysis of fas mutant embryos stained with anti-dCREB-A, the placodes appear morphologically identical to placodes of WT and hkb mutant embryos. At the stage when the dorsal-posterior pit forms in WT embryos, a slight indentation is observed near the center of the placode of fas mutant embryos, suggestive of cell shape changes. Although the initial indentation occurs at slightly variable locations in different embryos of similar age, the pit observed in late-stage fas mutants is trough-shaped and uniformly located close to the center of the placode. At late stages of embryogenesis, the overall morphology of the salivary glands of fas mutants is similar to that of hkb mutants; the glands are dome-shaped, are fused at the ventral midline and remain close to the embryo surface (Myat, 2000).

Although the salivary gland placodes of fas mutants appear identical to those of WT embryos at a gross morphological level, histological sections reveal significantly altered cell morphology. Instead of the monolayer of uniformly elongated epithelial cells that is observed in sections of WT embryos, placode cells in fas mutants are found in multiple layers, and are variably elongated. At later stages, the pit that forms in fas mutants is not as deep or wide as the pits of WT or hkb mutant embryos. Cells at the center of the pit appear elongated with basally positioned nuclei; however, the surrounding cells in the pit are round and found in multiple layers. Cells in the anterior and posterior parts of the gland also form multi-layered placodes. The salivary glands of fas mutants are eventually internalized, despite gross abnormalities in cell shape. The internalized gland is comprised of a mixture of elongated and wedge-shaped cells. Cells in the anterior and posterior parts of the gland are multi-layered. After internalization, the fas mutant salivary glands fuse into one dome-shaped organ, which is located close to the ventral surface, like the glands of hkb mutant embryos. Unlike the salivary gland cells of WT and hkb mutants, salivary gland cells of fas mutant embryos are not in an epithelial monolayer and, instead, appear to have condensed into a single, multilayered organ with remnants of a potentially contiguous lumen. As in the hkb mutant embryos, potential secretory products, indicated by dark Methylene Blue staining, are found in the lumen of fas mutant embryos (Myat, 2000).

Since fas and hkb mutant embryos have similar salivary gland phenotypes at a gross morphological level, and hkb encodes a transcription factor, the expression of fas was examined in both WT and hkb mutant embryos. Prior to invagination, FAS mRNA and protein are expressed in all secretory cells in WT embryos. At the start of invagination, FAS mRNA levels decrease to the levels observed in surrounding epithelial cells, and it is no longer detected in cells that have been internalized. At this stage, higher levels of Fas protein are detectable in all secretory cells, including the invaginating dorsal-posterior cells, relative to surrounding non-salivary gland cells. Fas protein is detected in all secretory cells that have internalized, and this level is maintained throughout the remainder of embryogenesis. Fas protein levels appear highest at the apical membrane, although different fixation procedures alter the relative levels of protein detected. The early expression of FAS mRNA and protein are unchanged in embryos mutant for hkb. Later, when elevated levels of Fas protein are observed in the invaginating dorsal-posterior cells of WT embryos, such elevated levels are instead observed in cells at the center of the glands in hkb mutants, and these cells are the first to internalize. In the internalized secretory cells, the level of Fas appears equivalent in hkb mutants and WT embryos. Thus, hkb affects fas expression transiently and only indirectly, by specifying the order in which secretory cells are internalized (Myat, 2000).

In hkb mutant embryos, salivary gland primordial cells undergo the characteristic cell shape changes and invaginate, albeit in a different region of the placode. This phenotype suggests that in the absence of Hkb acting as an instructive signal, cells may activate a default mechanism for invagination. Invagination of the central cells in the salivary gland placode of hkb and fas mutant embryos could be due to an as yet unidentified molecule whose expression is independent of hkb, and which mediates cell shape change in only these central cells. Such a molecule would only be active in the absence of hkb function, leading to the invagination of the central cells first. forkhead (fkh) encodes a transcription factor whose early expression in the salivary gland placodes is Hkb-independent. The salivary glands are not internalized in fkh mutant embryos although the first cell shape changes are initiated at the right position in the primordia. This phenotype suggests that Fkh may normally fuel internalization, perhaps providing sufficient force to direct internalization at an ectopic site in the absence of hkb function (Myat, 2000).


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huckebein: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 20 August 2012

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