extra macrochaetae

DEVELOPMENTAL BIOLOGY

Embryonic

See the embryonic expression pattern of emc at the Berkeley Drosophila Genome Project Patterns of Gene Expression Site.

EMC is supplied maternally and produced at all stages in embryos as well (Ellis 1980 and Garrell, 1990). emc is expressed in complex patterns in the three embryonic layers. Expression of emc often precedes and accompanies morphogenic movements involved in gastrulation. Examples are the cephalic and ventral furrows, amnioproctodeal invagination, anterior midgut primordium, dorsal folds, invaginating stomodeum, tracheal pits and the intersegmental grooves. Paradoxically, the mRNA is virtually absent from the ectodermal layer from which neuroblasts segregate. Other regions of abundant emc expression are the mesodermal layer, visceral mesoderm and rudiments of Malpighian tubules and muscle attachment sites (Cubas 1994 and Ellis 1994).

Larval

Both hairy and emc negatively regulate morphogenetic furrow progression in the developing eye. Both are expressed ahead of the morphogenetic furrow (Brown 1995).

Adult

The pattern of adult sensilla is promoted by achaete-scute complex and daughterless, and is suppressed by emc and hairy (Moscoso del Prada 1984).

Effects of Mutation or Deletion

emc mutant embryos do not hatch and their cuticle displays multiple alterations. emc is required for proper formation of intersegmental grooves, apparently due to defects in muscle development. With emc mutation, accumulation of Fasciclin III is reduced.

Just before the start of germ band retraction [Image], spatial distribution of neuroblasts and their descendants (the ganglion mother cells) are found to be more disorganized than in wild type; later axonal patterns are anomolous (Cubas, 1994). Malpighian tubules are rudimentary and some muscles are missing or disrupted. emc controls and limits cell proliferation within the inter-vein region of the wing, with similar effects on haltere and leg (de Celis, 1994).

A genetic and phenotypic analysis of the gene pannier is described. Animals mutant for strong alleles die as embryos in which the cells of the amnioserosa are prematurely lost. This leads to a dorsal cuticular hole. The dorsal-most cells of the imagos are also affected: viable mutants exhibit a cleft along the dorsal midline. Pannier mRNA accumulates specifically in the dorsal-most regions of the embryo and the imaginal discs. Viable mutants and mutant combinations also affect the thoracic and head bristle patterns in a complex fashion. Only those bristles within the area of expression of pannier are affected. A large number of alleles have been studied; they reveal that pannier may have opposing effects on the expression of achaete and scute leading to a loss or a gain of bristles. Certain alleles of pannier are sensitive to the dose of extra-machrochaetae. In those parts of the epithelium where both are present, it is possible that pnr and emc function together in the same ac-sc repression pathway (Heitzler, 1996).

emc is required during wing cell proliferation and vein differentiation. Mosaic analysis of hypomorphic emc reveals the tendency of mutant cells to proliferate along veins as long stripes. Large clones abuting two adjacent veins obliterate the corresponding inter-vein, affecting the size and shape of the whole wing. Thus, the emc gene participates in the control of cell proliferation within inter-vein regions in the wing. Similar effects are found in the haltere and the leg. The behavior of emc cells in genetic mosaics indicates that (1) proliferation is locally controlled within inter-vein sectors, (2) cells proliferate according to their genetic activity along preferential positions in the wing morphogenetic landscape, and (3) cell proliferation in the wing is integrated by 'accommodation' between mutant and wild type cells (de Celis, 1995).

How do veins on the dorsal and ventral surfaces of a fly's wing line up in exact opposition to one another? The adult Drosophila wing consists of two wing surfaces, apposed by their basal membranes, which first come into contact at metamorphosis, following wing disc eversion. Contact is crucial. Veins normally appear in these surfaces in a dorsal-ventral symmetric pattern, but when contact between the two surfaces is prevented, the dorsal-ventral pattern of venation takes on a 'corrugated,' asymmetric appearance (vein cells are more compacted and more pigmented). Dorsal-ventral contact apposition was prevented during wing imaginal disc morphogenesis by implanting fragments of discs into metamorphosing hosts. In these implants, longitudinal veins differentiate in both surfaces, but exhibit wider than normal corrugation. These results and those of genetic mosaics for mutants that remove veins or cause ectopic veins, reveal mutual dorso-ventral induction/inhibition at work to modulate the final vein differentiation pattern and/or corrugation. While clones of mutants causing a lack of veins (the single mutant rhomboid, the double mutant rhomboid vein, and the triple mutant extramachrochaetaeAch rhomboid vein) are autonomous in both wing surfaces, the vein phenotype is partially rescued by wild type cells from the opposite surface. When apposed to a lack of vein differentiation in the dorsal surface, vein differentiation fails in distal vein territories, preferentially in the ventral surface. Conversely, extra differentiation as in plexus, extramachrochaetae, HS-rhomboid 27B, Notch and Delta mutants, causes extra veins in clones, not only in the wing surface of the clone, but also in the opposite wing surface. Non-autonomous effects are observed in the same wing surface, a phenomenon called 'connectivity'. Genetic mosiacs of plexus72 and emc HS-rho27B cause neighboring non-mutant cells on the same surface to differentiate extra veins, connecting them. Cis (planar) and trans (vertical) effects may be operationally related, inducing contacting cells to differentiate vein histotypes. Vein cells induce vein differentiation in neighbouring cells, either on the same surface by planar cell-cell communication, or on the opposite surface through signals along the basal membrane of the apposing epithelium. Thus, although the vein pattern is surface-autonomously generated, inhibitory (negative) and inductive (positive) signals take place between both dorsal and ventral wing surfaces in order to refine the final vein pattern with the corresponding dorso-ventral wing surfaces (Milan, 1997).

Wingless and Decapentaplegic cell signaling pathways act synergistically in their contribution to macrochaete (sense organ) patterning on the notum of Drosophila. The analysis of the origin of sense organ precursor prepatterning has focussed on the specification and positioning of the anterior and posterior dorsocentral macrochaetes (aDC, pDC) two large mechanosensory organs located in precise positions relative to surrounding rows of microchaetes. The aDC and pDC SOPs form sequentially on the proximal edge of a single DC proneural cluster where Achaete and Scute expression depends on a cis-activating enhancer sequence, the DC enhancer. Ac expression in the DC proneural cluster requires the activity of wingless. The DC SOPs form adjacent to the stripe of cells expressing wg in the presumptive notum during the third larval instar. To probe the nature of gene interaction required for macrochaetae formation, the Wingless-signaling pathway was ectopically activated by removing Shaggy activity (the homolog of vertebrate glycogen synthase kinase 3) in mosaics. Proneural activity is asymmetric within the Shaggy-deficient clone of cells and shows a fixed polarity with respect to body axis, independent of the precise location of the clone. This asymmetric response indicates the existence in the epithelium of a second signal, possibly Decapentaplegic. Ectopic expression of Decapentaplegic induces extra macrochaetes only in cells that also receive the Wingless signal. Outside the Wg-activated domain, in the medial scutum and prescutum, clones that ectopically express Dpp make only microchaetes. In the Wg-activated domain, within and lateral to the DC meridian, clones of cells ectopically expressing dpp are associated with many extra macrochaetes, which are formed both within and around the Dpp-expressing clones. It is concluded that in areas of the notum where the WG transduction pathway is inactive, Dpp alone is insufficient for macrochaete formation. Activation of Hedgehog signaling generates a long-range signal (Dpp) that can promote macrochaete formation in the Wingless activity domain. This signal depends on decapentaplegic function. Autonomous activation of the Wingless signal response in cells causes them to attenuate or sequester this signal. Extramacrochaetae (a proneural antagonist) is required to limit the anterior/posterior extent of this cluster. If the level of emc is reduced, extra macrochaetes form primarily anterior but also posterior to the normal DCs along the proximal edge of the wg stripe. Further reduction of emc results in additional extra macrochaetes along the dorsal edge of the stripe. These results suggest a novel patterning mechanism that determines sense organ positioning in Drosophila (Phillips, 1999).

A role for extra macrochaetae downstream of Notch in follicle cell differentiation

The Drosophila ovary provides a model system for studying the mechanisms that regulate the differentiation of somatic stem cells into specific cell types. Ovarian somatic stem cells produce follicle cells, which undergo a binary choice during early differentiation. They can become either epithelial cells that surround the germline to form an egg chamber ('main body cells') or a specialized cell lineage found at the poles of egg chambers. This lineage goes on to make two cell types: polar cells and stalk cells. To better understand how this choice is made, a screen was carried out for genes that affect follicle cell fate specification or differentiation. extra macrochaetae (emc), which encodes a helix-loop-helix protein, was identified as a downstream effector of Notch signaling in the ovary. Emc is expressed in proliferating cells in the germarium, as well as in the main body follicle cells. Emc expression in the main body cells is Notch dependent, and emc mutant cells located on the main body fail to differentiate. Emc expression is reduced in the precursors of the polar and stalk cells, and overexpression of Emc caused dramatic egg chamber fusions, indicating that Emc is a negative regulator of polar and/or stalk cells. Emc and Notch are both required in the main body cells for expression of Eyes Absent (Eya), a negative regulator of polar and stalk cell fate. It is proposed that Emc functions downstream of Notch and upstream of Eya to regulate main body cell fate specification and differentiation (Adam, 2004).

EMC has a complex pattern of expression. emc^P5C-lacZ is expressed in the terminal filament and inner sheath cells of the germarium, and in the main body follicle cells of egg chambers, but not in the early follicle cells or in polar or stalk cells. An anti-Emc antibody revealed additional features of Emc expression: Emc is expressed in the undifferentiated follicle cells of the germarium. Its expression is reduced in follicle cells in the intercyst regions between region 2 and region 3 cysts. It is maintained in main body cells but further reduced in stalk and polar cells of stage-1-4 egg chambers. Its expression in stalk cells remains low, but, in polar cells after stage 4, returns to a level indistinguishable from that exhibited by their neighbors. The overall level of expression is somewhat reduced from stage 6 to stage 8, and at stage 9 expression in the oocyte-associated follicle cells is further reduced, although still detectable (Adam, 2004).

There are number of similarities in the phenotypic effects of Notch and Emc in egg chamber development; it is concluded that Emc is a downstream effector of Notch in the differentiation of follicle cells. In other tissues, genes of the Enhancer of split complex are major downstream effectors of Notch signaling, but they do not appear to be required for differentiation of the follicle cells. By contrast, Emc is expressed in most somatic cells of the ovariole and has a loss-of-function phenotype similar to that of Notch. Like Notch, Emc is required for the formation of polar cells, and egg chambers lacking polar cells are observed at one end when emc clones are generated. emc mutant cells also fail to downregulate Fas3 expression at stage 6, and the cells fail to enter endoreplication at the proper time, indicating that emc is required for follicle cell differentiation. In addition, Emc expression in the main body follicle cells is dependent on Notch and can be induced by forced expression of activated Notch. Taken together, this leads to the proposal that Emc is an effector of Notch activity in follicle cells (Adam, 2004).

Notch and Emc are both involved in separation of adjacent egg chambers. Follicles mutant for Notch or emc include egg chambers containing multiple germline cysts and lacking intervening polar and stalk cells. Recent work has shown that Notch signaling is not required for early packaging (enveloping of the cyst by follicle cells), but its role in specifying polar/stalk precursors, which might occur subsequent to packaging, has not been addressed specifically. However, Notch is required autonomously for polar cell differentiation, and at least one pair of differentiated polar cells is required to induce a stalk. Therefore, the packaging defects observed in Notch mutants may be due solely to either the failure of polar cells to differentiate or to a particular role in specifying polar/stalk precursors. The fused egg chambers observed in emc mutants could also be due to a role in one or both processes. If emc were involved separately in both processes, then a dramatic increase would be expected in the frequency of fused egg chambers when clones were generated in the germarium, where precursors are formed. Since no such increase was seen, a role for emc in polar/stalk precursor formation is not posited; however, without a better understanding of polar/stalk precursors, this cannot be confirmed (Adam, 2004).

emc is probably not the only effector downstream of Notch in the ovariole, since emc mutant clones exhibit some differences from Notch mutant clones. In general the effects of emc are less penetrant than those of Notch. For example, emc mutant cells, like Notch mutant cells, exhibit persistent Phosphohistone H3 and Cyclin B labeling but at low frequency and at low levels. In addition, although emc is involved in polar cell specification or differentiation, it is only partially required for this, since normal polar cells could be observed even in clones of a null emc allele. Thus, there are likely to be additional downstream effectors of Notch in the ovary (Adam, 2004).

Molecular epistasis indicates that Notch signals through Emc to induce or maintain Eya expression in the main body follicle cells. Eya expression is lost in large Notch mutant follicle cell clones and can be induced by forced expression of activated Notch in the follicle cells. Eya is involved in inhibiting polar and stalk cell fate, so one might expect that Notch or emc loss-of-function mutants would make extra polar cells. This is not the case, however; it seems likely that the reason Notch and emc mutant cells do not become polar cells is that they fail to differentiate. Eya does not appear to be required for differentiation, but rather for main body cell fate, since eya mutant cells differentiate into polar cells. Thus, the Notch pathway must branch downstream of Emc, with one pathway leading to Eya expression and repression of polar cell fate, and a separate pathway leading to differentiation (Adam, 2004).

Emc can have both positive and negative effects on the number of polar cells. Although this might initially seem mysterious, it can be explained by the dynamic expression of Emc in ovaries. Emc is expressed in the germarium, but it is reduced in polar/stalk precursors. Its expression remains low in stalk cells but, in polar cells, returns to the same level as that of their neighbors around the time of differentiation. Temperature-shift experiments show that forced expression of Emc in immature polar cells can lead to expression of Eya, which is the presumed cause of loss of polar cells. By contrast, forced expression of Emc in maturing polar cells appears to lead to potentiation of polar cell number, i.e., polar cell number per group is not reduced from four to two, as in wild-type, but remains at four polar cells per group. This is probably due to a role for Emc in polar cell differentiation, because loss-of-function emc clones can result in loss of polar cells (Adam, 2004).

Three lines of evidence suggest that Emc may be a key regulator of Eya expression. (1) Emc and Eya expression are similar in multiple respects. Both are upregulated in follicle cells in region 2B of the germarium, and in main body follicle cells from stages 2 through 6. Both are downregulated in the polar/stalk lineage from the germarium through stage 3, and in the oocyte-associated follicle cells at stages 7 through 9. (2) Emc is required for Eya expression in the main body. (3) Emc and Eya produce similar overexpression phenotypes, including fused egg chambers and the loss of polar cells, and, when Emc is overexpressed in the polar cells, Eya expression is induced. Taken together, these data suggest that the expression of Eya in the follicle cells is largely regulated by Emc. Emc is a helix-loop-helix protein that lacks the basic DNA-binding domain of the bHLH transcription factors. It normally opposes the activity of bHLH transcription factors by sequestering them in non-productive complexes. Thus, the dependence of Eya on Emc is likely to be indirect. Presumably, Emc inhibits a bHLH protein that inhibits expression of Eya. The identity of this protein remains an interesting subject for further study (Adam, 2004).

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date revised: 15 August 2009

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