empty spiracles

DEVELOPMENTAL BIOLOGY

Embryonic

A 2.4 kb RNA corresponding to the EMS transcript is expressed from cellular blastoderm throughout all embryonic and larval stages. During the cellular blastoderm stage ems is expressed in the developing head in a single anterior band, overlapping the domain of Deformed. Later in development this site can be identified as just anterior to and extending along the whole cephalic furrow. This location correlates with EMS function as an anterior gap gene, expressed in the preantennal, antennal and intercalary segments [Images] and required for the development of the antennal sense organ, the optic lobe and parts of the head skeleton. Later still ems is expressed segmentally in the clypeolabrum, the lateral regions of the procephalic lobe, and in three gnathal, as well as three thoracic and 10 abdominal segments. Expression is confined to lateral regions of each segment, where the tracheal pits form and lateral neuroblasts originate, as well as in the posterior spiracles. This late expression partially correlates with defects seen in the tracheal tree of ems null embryos ( Dalton, 1989 and Walldorf, 1992).

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).

During early neurogenesis in the trunk, empty spiracles (ems) is metamerically expressed in lateral ectodermal patches. In the head, it acts as a gap gene, which is expressed in a circumferential procephalon domain in the early cellular blastoderm. During gastrulation this circumferential stripe dissolves into three smaller ectodermal domains between the anterior part of the mandibular segment and the posterior part of the ocular segment; these domains are not in segmental register. During further development, the third domain splits into a mandibular/intercalary and an antennal component. All these domains contribute NBs to the brain. In addition to ems expression in the intercalary and antennal segments, and the corresponding trito- and deutocerebral neuromers, ems expression was also detected in a small neuroectodermal region. Finally, a further ems patch is located in the dorsoanterior procephalic ectoderm ('dorsal patch'), which becomes part of the labral ectoderm and does not appear to give rise to brain NBs. Thus, from stage 9 onwards, part of the antennal/ocular ems domain overlaps with the En-positive hs, and from stage 10/11 onwards these genes are also found to be co-expressed in the en hs-derived protocerebral NBs Ppd5 and Ppd8 (although en and ems expression also partly overlaps in the trunk ectoderm, a co-expression of both genes in trunk NBs is never seen). In contrast to earlier observations, showing that most of the tritocerebral NBs are included in the ems-expressing domain, only the dorsal Td6 was identified as Ems-positive. Ems protein is detectable in clusters of brain cells until the end of embryogenesis (Urbach, 2003).

Taken together, among the cephalic gap genes, slp1 appears to respect segmental boundaries during early neurogenesis of the brain. By contrast, in the considered period of development (stage 9-11), the expression of ems, otd and tll does not seem to respect these borders, contradicting claims in previous reports. All three genes are expressed in NBs deriving from ectodermal domains that are part of two or three neighboring segments. For example, ems is expressed in a small number of NBs comprising about six posterior ocular and four anterior deutocerebral NBs (all of which derive from the same ems domain, except Dv3 and Pcv5), and one tritocerebral NB. Accordingly, ems mutants show defects in the intercalary, antennal, and the ocular segment (e.g., the en hs is missing). Considering that ems is expressed in only a few trito- and deuto-cerebral NBs it is remarkable that ems mutants show a deletion of the trito- and deuto-cerebrum. An explanation for this could be that ems expression, which during earlier development covers the neuroectoderm of the respective segments, possibly confers specific identities to the arising trito- and deuto-cerebral NBs. The lack of these NBs might be responsible for the loss of NB-specific gene expression, and (secondarily) for the gross morphological defects seen in the ems mutant brain. A similar proposal has been made to explain the brain defects that occur in buttonhead (btd) mutants, although btd is not expressed in NBs of the corresponding brain regions (Urbach, 2003).

Effects of Mutation or Deletion

Structural and functional comparisons between ems and other embryonic patterning genes of Drosophila suggest that ems acts, in part, as a homeotic selector gene, specifying the identity of some of the most anterior head segments. Mutant embryos lacking EMS protein have severe patterning defects in the anterior head and are missing tracheal structures, including the filzkörper, which are normally developed by the eighth abdominal segment (Dalton, 1989).

ems is required for the development of specific brain segments in Drosophila. The embryonic brain is composed of three segmental neuromeres. The orthodenticle gene is expressed predominantly in the anterior neuromere; expression of ems is restricted to the two posterior neuromeres. Mutation of otd eliminates the first (protocerebral) brain neuromere. Mutation of ems eliminates the second (deutocerebral) and third (tritocerebral) neuromeres. otd is also necessary for development of the dorsal protocerebrum of the adult brain (Hirth, 1995).

Cell lineage-specific expression and function of the empty spiracles gene in adult brain development of Drosophila melanogaster

The empty spiracles (ems) gene, encoding a homeodomain transcription factor, is a member of the cephalic gap gene family that acts in early specification of the anterior neuroectoderm in the embryonic brain of Drosophila. ems is also expressed in the mature adult brain in the lineage-restricted clonal progeny of a single neuroblast in each brain hemisphere. These ems-expressing neuronal cells are located ventral to the antennal lobes and project a fascicle to the superior medial protocerebrum. All adult-specific secondary neurons in this lineage persistently express ems during postembryonic larval development and continue to do so throughout metamorphosis and into the adult. Mosaic-based MARCM mutant analysis and genetic rescue experiments demonstrate that ems function is autonomously required for the correct number of cells in the persistently expressing adult-specific lineage. Moreover, they indicate that ems is also required cell autonomously for the formation of the correct projections in this specific lineage. This analysis of ems expression and function reveals novel and unexpected roles of a cephalic gap gene in translating lineage information into cell number control and projection specificity in an individual clonal unit of the adult brain (Lichtneckert, 2007).

During postembryonic development of the Drosophila brain, expression of the ems gene is observed in eight neuroblast lineages per hemisphere. In seven of these, ems expression is transient and disappears during pupal development. This cessation of expression during metamorphosis could be related to the dynamic pattern of ems expression within each lineage. Thus, during larval development of these lineages, ems expression appears limited to the neuroblast and its recently generated progeny, suggesting that expression in the progeny may be transient. This type of dynamic expression could explain the fading out of the Ems signal in the seven lineages once their neuroblasts stop proliferation at the early pupal stage (Lichtneckert, 2007).

By contrast, in the eighth neuroblast lineage, ems expression is persistent. During larval development the neuroblast and all its adult-specific progeny express ems; this expression continues throughout metamorphosis and into the adult in all postmitotic cells of the EM lineage. The mechanisms responsible for the maintenance of ems expression in the adult-specific cells of the EM lineage are currently unknown. However, there is some evidence that ems is also expressed and maintained in the primary neurons of the EM lineage generated during embryogenesis. In all postembryonic stages and in the adult, approximately 30 ems-expressing neurons are closely associated with the early born, adult-specific neurons of the EM clone. These neurons are not generated postembryonically, and their number does not change significantly during postembryonic development. This suggests that the mechanisms responsible for the persistence of ems expression in the EM lineage may operate in all cells of the lineage, embryonic and postembryonic (Lichtneckert, 2007).

During early embryogenesis, ems is expressed in a total of eleven neuroblasts per embryonic brain hemisphere. An unambiguous link between these embryonic brain neuroblasts and the eight postembryonic ems-expressing neuroblasts has not yet been established. If the persistent expression of ems is a unique feature of the EM lineage, it should be possible to trace this lineage back into embryonic stages and identify its embryonic neuroblast of origin. For the remaining seven postembryonic ems-expressing neuroblasts, this may be more difficult and require a combination of molecular markers and neuroanatomical lineage mapping (Lichtneckert, 2007).

The postembryonic expression of ems in the fly brain has interesting parallels to the expression of the Emx1 and Emx2 genes in the mammalian brain. In addition to early expression in the neural plate, the Emx1 gene is expressed in many differentiating and mature neurons of the murine cortex. Brain-specific expression of Emx2 appears to be more transient in later stages and in the adult brain seems to be restricted to neural stem cells. Thus, spatially restricted persistent and transient expression patterns are observed for the ems/Emx genes in neural progenitors and in neurons during brain development and maturation in flies and mice (Lichtneckert, 2007).

For mutant analysis of ems function focus was placed on the EM lineage and clonal techniques were used to ensure that the secondary adult-specific neurons are mutant from the time of their birth onwards. Two lineage-specific mutant phenotypes are apparent in these loss-of-function experiments. The number of adult-specific neurons is reduced and projection defects occur in mutant clones. Both phenotypes are cell autonomous, and both can be fully restored in genetic rescue experiments. Moreover, both mutant phenotypes are seen in larval stages and persist in the adult brain. These findings implicate the ems transcription factor in translating lineage information into neuronal cell number control and neurite projection specificity (Lichtneckert, 2007).

There are several possible explanations for the 50% reduction in cell number observed in ems mutant EM clones. First, proliferation of the mutant neuroblast might cease due to cell cycle arrest or to premature neuroblast death. This seems unlikely, because proliferating neuroblasts can be identified in larval ems mutant clones based on expression of specific markers. Second, cell division of ganglion mother cells might be suppressed in favour of a direct differentiation of each neuroblast progeny into a single neuron, resulting in a total clone size reduction of 50%. This also appears unlikely, since GMCs expressing a cell proliferation marker can be identified repeatedly in mutant clones, indicating that they divide normally to produce two daughter cells. Third, the time window of proliferative activity or the proliferation rate of the persistent neuroblast is shortened in ems mutants. While this possibility cannot be ruled out, it also appears unlikely for the following three reasons: first, mutant and wild-type clones contain a similar number of cells at 48 hours ALH, suggesting that the proliferation rate is not affected at this stage; second, BrdU-incorporation studies reveal no difference in mitotic activity at late larval stage brains of wild-type versus ems mutant clones; third, the percentage of neuroblasts expressing the mitotic marker H3p at late larval stages was comparable for wild-type and ems mutant clones. The final explanation for the marked reduction in cell number seen in mutant clones is that postmitotic cells die due to apoptosis. This possibility is supported by two observations: (1) late larval ems mutant EM clones contain apoptotic cells, as assayed by the apoptosis marker cleaved Caspase 3 and (2) blockage of cell death in the ems mutant lineage through a pancaspase inhibitor results in significant restoration of the clonal cell number to a value comparable to that observed in the wild type. Based on these findings, it is posited that ems is required in the adult-specific EM lineage for survival of clonal postmitotic progeny (Lichtneckert, 2007).

Two types of neurite projection defects are observed in ems mutant EM lineages. (1) In the adult brain of all ems mutants, short aberrant projections extend from the cell bodies in a misdirected manner into adjacent neuropile. Misdirected projections of this type are also present in the larval ems mutant EM lineages. This suggests that ems is already required during larval stages to prevent the formation of these misprojections. Whether the aberrant projections formed in the larva persist into the adult, or whether misprojections of this type are continuously formed (and retracted) during metamorphosis and in the adult, is currently not known. However, the fact that neurite projections, albeit short and ectopic, are formed in all mutant EM clones implies that the ems gene is not required for process outgrowth per se. Rather, the ems gene appears to be required to prevent the formation of misdirected processes, suggesting a role of the gene in neuronal pathfinding (Lichtneckert, 2007).

(2) Another projection defect is observed in the adult brain in approximately half the ems mutant EM lineages. It consists in the complete absence of the fascicle projecting to the superior medial protocerebrum. This projection phenotype in the adult has a corresponding projection phenotype in the larva, in that the primary neurite bundle is missing in approximately half the mutant lineages. These observations suggest that the formation of the primary neurite bundle during larval development might be a prerequisite for the process extension to adult-specific targets during metamorphosis; this would indicate a larval requirement of ems for neurite fascicle formation (Lichtneckert, 2007).

Both projection phenotypes seen in mutant neuroblast clones, short ectopic neurite projections and the absence of the fascicle to the protocerebrum, are also apparent in ems mutant single cell clones of the larval brain. Given that all other cells in the lineage, including the EM neuroblast, are wild-type-like in these experiments, this finding indicates that individual postmitotic neurons of the EM lineage have a cell-autonomous requirement for the ems gene in order to form correct projections in larval brain development (Lichtneckert, 2007).

This analysis of ems function in the EM lineage demonstrates that homeobox transcription factors can influence adult brain architecture in a cell-autonomous and lineage-specific way. A lineage-specific, cell-autonomous requirement of other transcription factors in brain development has been shown for the olfactory projection neurons and for mushroom body neurons in Drosophila. Thus, increasing evidence indicates that key developmental control genes, which operate early in embryogenesis, also act later in a lineage-specific manner in controlling anatomical features of the adult Drosophila brain. It may be a general feature of brain development that developmental control genes implicated in early neurogenesis and patterning are re-expressed and have different roles in later embryogenesis and postembryonic brain development (Lichtneckert, 2007).

A comparison of the role of ems in Drosophila brain development with that of Emx1 and Emx2 in mammalian brain development is interesting, especially when the cortical phenotypes of Emx1/Emx2 double mutants are considered. The cortical surface area of Emx1/Emx2 double mutants is about half that of wild type, and the thickness of the preplate and cortical plate is reduced, suggesting that Emx genes regulate the numbers of cortical neurons. Moreover, Emx1/Emx2 double mutants have major defects in the pathfinding of most cortical axons, implying an important role for Emx genes in axonal pathfinding in the brain. Thus, mutant analyses in Drosophila and mouse suggest that loss of function of ems/Emx genes may result in comparable brain phenotypes, namely in reduction of neuronal cell number and in neurite projection defects. This in turn suggests that the morphological differentiation of brain architecture in both flies and mammals may involve conserved functions of orthologous ems/Emx homeobox genes, not only in the early embryo but also during later stages of brain development (Lichtneckert, 2007).

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Date revised: 15 January 2008





  

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