• Cephalic furrow or fold - the division between head and thorax
• Procephalic lobe - the pregnathal cephalic territory prior to segmentation
• Acron - the unsegmented preoral part of the head
• Atrium - Opening and most anterior portion of the foregut
• Gnathal - refering to the mouth appendage
• Stomodeum - the anterior ectodermal part of the gut
• Labella or labial palps - fleshy lobes that terminate the proboscus - the terminal part of the labium
• Proboscus - the sucking organ
• Optic placode - distinctive patch of cells that will form the eye-antennal disc
• Cephalopharyngeal apparatus - larval feeding organ consisting of mouth hooks, H Piece, medial tooth and cephalopharyngeal skeleton

The function of Dpp and Hh in partitioning the embryonic dorsal head neurectoderm

This region, referred to as the anterior brain/eye anlage, gives rise to both the visual system and the protocerebrum. The anlage splits up into three main domains: the head midline ectoderm, protocerebral neurectoderm and visual primordium. Similar to their vertebrate counterparts, Hh and Dpp play an important role in the partitioning of the anterior brain/eye anlage. Dpp is secreted in the dorsal midline of the head. Lowering Dpp levels (in dpp heterozygotes or hypomorphic alleles) results in a 'cyclops' phenotype, where mid-dorsal head epidermis is transformed into dorsolateral structures, i.e. eye/optic lobe tissue, which causes a continuous visual primordium across the dorsal midline. Absence of Dpp results in the transformation of both dorsomedial and dorsolateral structures into brain neuroblasts. Regulatory genes that are required for eye/optic lobe fate, including sine oculis (so) and eyes absent (eya), are turned on in their respective domains by Dpp. The gene zerknuellt (zen), which is expressed in response to peak levels of Dpp in the dorsal midline, secondarily represses so and eya in the dorsomedial domain. Hh and its receptor/inhibitor, Patched (Ptc), are expressed in a transverse stripe along the posterior boundary of the eye field. Hh triggers the expression of determinants for larval eye (atonal) and adult eye (eyeless) in those cells of the eye field that are close to the Hh source. Eya and So, which are induced by Dpp, are epistatic to the Hh signal. Loss of Ptc, as well as overexpression of Hh, results in the ectopic induction of larval eye tissue in the dorsal midline (cyclopia). The similarities between vertebrate systems and Drosophila are discussed with regard to the fate map of the anterior brain/eye anlage, and its partitioning by Dpp and Hh signaling (Chang, 2001).

At the onset of gastrulation, the anlage that gives rise to the anterior brain (protocerebrum) and the eye, roughly defined by the expression of otd, extends from the cephalic furrow to the anlage of the foregut. In the dorsoventral axis, the anlage crosses the dorsal midline; laterally it reaches to ~50% of egg diameter where it is bounded by the ventral neurectoderm. During gastrulation and germband elongation, the anlage splits up into different components that can be recognized morphologically and with the help of molecular markers. Three main domains, the head midline ectoderm, protocerebral neurectoderm and the visual primordium, can be distinguished (Chang, 2001).

A narrow strip straddling the dorsal midline gives rise to the medial portion of the head epidermis. In the acephalic larva, these cells (and most other cells of the head epidermis) are folded inside the animal to form the dorsal pouch (Chang, 2001).

The lateral part of the head neurectoderm produces the neuroblasts that form the central protocerebrum, the major compartment of the insect brain that includes associative centers such as the mushroom bodies and central complex. A narrow domain within the dorsomedial protocerebrum is the anlage of the so-called pars intercerebralis, which contains clusters of neuroendocrine cells producing various neuropeptides. The neuroendocrine neurons project their axons in a peripheral nerve that leaves the brain and reaches the corpora cardiaca, a neurohemal organ located close to the heart. The pars intercerebralis-corpora cardiaca system is highly reminiscent of the vertebrate hypothalamus-pituitary axis, and this similarity extends to the embryonic origin of the corpora cardiaca. Thus, the corpora cardiaca arise as invaginations from the foregut. Their embryonic origin has been well documented in Manduca sexta; in Drosophila, the corpora cardiaca, along with precursors of the stomatogastric (i.e. autonomic) nervous system, also invaginate from the foregut (Chang, 2001).

The visual primordium, defined molecularly by the expression of so, is wedged in between the midline ectoderm and the protocerebral neurectoderm in the posterior head. During gastrulation and germband extension, cells of the visual primordium move laterally and are subdivided into the larval and adult eye primordia and the inner and outer optic lobe. The optic lobe and larval eye form a triangular placode that invaginates. The posterior lip of this invagination, marked by the expression of FasII, represents the primordium of the lamina and medulla, and gives rise to the lobula complex. The larval eye, or Bolwig's organ, labeled by FasII and mAb22C10, develops at the lateralmost tip of the optic lobe placode. The cells that will become the eye imaginal disc (adult eye) are anterior and dorsal to the optic lobe placode and can be recognized by the expression of eyeless (Chang, 2001).

Dpp expression and function were followed using an in situ RNA probe and an antibody against phosphorylated MAD protein (anti-pMAD), respectively. The patterns revealed by both markers in the embryonic head match closely, supporting the notion that dpp itself is a target of Dpp signaling. Dpp is expressed at the blastoderm stage in the entire dorsal half of the trunk and head of the embryo. Subsequently, the level of dpp and pMAD is elevated in a narrower dorsomedial stripe that includes the eye field. With the onset of gastrulation throughout the early extended germband stage (stages 7-10), dpp disappears from most of the head, except for an anterior domain in the anlage of the foregut, and a narrow posterior domain bordering the visual primordium posteriorly. This domain is contiguous with a dpp-expressing domain in the dorsal ectoderm of the trunk. During the late extended germband (stage 11) there appears a mid-dorsal domain of dpp expression in the posterior head, overlapping with prospective head epidermis. In addition, laterally, dpp appears in a small discrete spot in the antennal segment, immediately adjacent to the visual primordium. Based on this expression pattern, it is anticipated that the distribution of the Dpp protein in the head may be complex, and may shift during development from a dorsoventral gradient (early phase) over a posteroanterior gradient (intermediate phase) to a local point source (late phase) (Chang, 2001).

In the trunk, the effect of Dpp is inhibited in the ventral ectoderm by the Chordin homolog Sog and the transcriptional repressor Brk. Since the spatial control of the Dpp gradient in the head is likely to be influenced by the same players, the expression pattern of these genes in the embryonic head was investigated. At the blastoderm stage, sog and brk are expressed in the ventral half of the embryo along the entire anteroposterior axis. During gastrulation, expression in the head gradually spreads dorsally. At the extended germband stage sog and brk expression at a low level covers the protocerebral neurectoderm. sog disappears from the head during stage 11, while brk remains on somewhat longer. Note that the dorsal expression of sog and brk comes on later than the downturn of Dpp, which is complete with the onset of gastrulation. This suggests that the repression of dpp in the dorsal head is effected by factors in addition to Sog and Brk. Support for this hypothesis comes from the observation that in brk;sog double mutants, dpp expression does not expand into the protocerebral ectoderm, although it does cover most of the ventral ectoderm (Chang, 2001).

Loss, reduction and overexpression of Dpp in the head ectoderm results in a phenotype that can be most easily interpreted by assuming that similar to what has been postulated for the trunk, there is a graded requirement for Dpp at dorsomedial and dorsolateral levels. Reduction of Dpp function, as seen in the dpp hypomorph dpp^E87, or embryos lacking sog, results in a highly characteristic 'cyclops' phenotype. The dorsal epidermis that normally forms the dorsal pouch is absent, as evidenced by the loss of expression of the gene race that normally appears in the amnioserosa and dorsomedial head epidermis. Head epidermis is replaced by ectopic optic lobe and larval eye tissue which are exposed at the surface because head involution fails to occur. The pattern of protocerebral neuroblasts, visualized by anti-Sna antibody, is unchanged in dpp^E87, unlike the situation in dpp-null embryos where neuroblast levels are strongly increased. These findings imply that, similar to the amnioserosa of the trunk, the epidermal midline ectoderm of the head requires the highest levels of Dpp. Reduction of Dpp results in the transformation of the midline to dorsolateral structures that, in the head, are represented by the visual primordium (Chang, 2001).

A different and much more severe phenotype results from the total absence of Dpp. As in dpp hypomorphs, head midline epidermis does not form; however, instead of dorsolateral fates replacing the head midline fates, both midline and dorsolateral regions exhibit characteristics of lateral neurectoderm. Optic lobe and Bolwig's organ are absent. Neuroblasts are formed in realms of the head midline and visual system. To what dorsoventral level does the fate of the ectopic neural tissue correspond? The neurectoderm of the head gives rise to neuroblasts at ventrolateral levels (tritocerebrum and deuterocerebrum), as well as dorsolateral levels (protocerebrum). Based on the expression pattern of the markers ey, FasII and ind, it is concluded that the ectopic neuroblasts in dpp^- embryos appear to be of dorsolateral provenance. Thus, ind is normally expressed in the stage 9 wild-type embryo in a small dorsolateral cluster that gives rise to several protocerebral neuroblasts, as well as the anterior lip of the optic lobe. In dpp^-, ind-expressing cells are displaced to the dorsal midline (Chang, 2001).

The ubiquitously expressed driver line daughterless (da)-Gal4 was used to express UAS-dpp. This Gal4 line is not expressed in the blastoderm but comes on with gastrulation. Correspondingly, the resulting changes in cell fate in the head and trunk are relatively mild and can be best described in terms of a ubiquitously raised base level of Dpp, superimposed on the regular gradient of endogenous Dpp. Mid-dorsal structures, including the amnioserosa and head epidermis, were much wider than in wild type. Dorsolateral structures, including the visual primordium, are relatively normal in size and shape, but are shifted to lateral or ventrolateral levels. Ventral tissues are partially missing (Chang, 2001).

Overexpression of dpp by using the heat-inducible driver line hs-Gal4 results in a phenotype very similar to the one described for da-Gal4-driven UAS-dpp. Applying 2 hour heat pulses at different stages of development supports the idea that the phenocritical period of Dpp action is around the onset of gastrulation. Thus, a high number of embryos heat pulsed between 3 and 5 hours post fertilization show the characteristic dorsalization phenotype described above. Later heat pulses had no effect on head patterning (Chang, 2001).

The above described phenotypic effects observed in mid- and late-stage mutant embryos indicate that dorsal epidermal and visual system fates, in particular those of the posterior optic lobe and larval eye, are not expressed in dpp loss of function. It is likely that these abnormalities are the result of changes in early head gene expression. This was followed in detail by assaying the expression of several regulatory genes known to be required for the normal development of the visual primordium, including otd, tll, so and eya in dpp-null mutants:

1. otd is normally expressed in a wide domain that spans the dorsal midline and encompasses the entire dorsal head ectoderm. In normal development, its expression is turned off in the head midline (the head epidermis precursors) and in the part of the visual primordium forming the posterior optic lobe and larval eye. In dpp mutants, expression persists in the entire dorsal head ectoderm until stage 11. Expression then becomes patchy as many cells undergo apoptotic cell death (Chang, 2001).
2. tll appears in the protocerebral ectoderm, including the head midline ectoderm. Only later does expression spread to cover part of the visual primordium. In embryos that lack Dpp, expression is expanded from the beginning to include the entire dorsal head. As for otd, expression also persists in the head midline ectoderm (Chang, 2001).
3. so is expressed in a transverse stripe spanning the dorsal midline. This unpaired domain defines the eye field. Around gastrulation, so expression ceases in the dorsal midline and becomes restricted to the bilateral visual primordia. In addition to the visual system, so appears in the anlage of the stomatogastric nervous system (SNS) and head mesoderm. In a dpp-null fly, so is never expressed in the anlage of the visual system, although expression in the SNS and head mesoderm is unchanged (Chang, 2001).
4. eya is normally expressed in a complex pattern that essentially consists of three domains located in the anlage of the SNS, the anterior protocerebrum and the anlage of the visual system. In dpp-null embryos, eya expression in the primordia of the visual system and SNS is absent from the beginning. The anterior protocerebral expression is narrowed (Chang, 2001).

The observed downregulation of head gap genes and early eye genes in the dorsal midline is an indirect effect of Dpp mediated by the Dpp target zerknüllt (zen). Previous studies have demonstrated that high levels of Dpp in the dorsal midline upregulate and focus the expression of zen in the amnioserosa and, further anteriorly, in the dorsomedial head epidermis. An RNA in situ probe revealed the expression of zen in the early eye field of a stage 5-7 embryo. Assaying the expression of head gap and early eye genes in a zen-null mutant background demonstrates that Zen acts as a repressor of these genes. Whereas in wild type, after an initial unpaired expression straddling the dorsal midline, tll, so and eya are turned off in the dorsal midline, they continue to be expressed in this domain in a zen mutant. At later stages, lack of zen results in a cyclops phenotype (Chang, 2001).

Hh is expressed in metameric stripes that coincide with the posterior compartment of each segment. In the head, hh expression in the stage 5-7 embryo forms a wide stripe in front of the cephalic furrow. This stripe, which crosses the dorsal midline, includes the future antennal segment and posterior part of the visual anlage. As germ band extension proceeds, hh expression disappears from the dorsal midline and two separate bands are parceled out (antennal stripe, pre-antennal or occular stripe). The pre-antennal stripe overlaps with the lateral boundary of the visual primordium. Towards the late extended germband stage, the Hh head domain decreases in size and expression level. During stage 11 and early 12, only a small cluster of cells corresponding to the precursors of the larval eye located laterally in the visual primordium remain hh positive (Chang, 2001).

Hh signaling is negatively regulated by Ptc, a membrane linked protein that, by binding to Hh ligand, becomes inactivated in cells receiving high levels of Hh. Ptc expression in the head resembles hh expression at an early stage. A wide antennal/pre-antennal stripe traverses the head in front of the cephalic furrow. During germband extension, this domain splits into two stripes. At the late extended germ band stage, ptc remains expressed in a large domain that corresponds to the anterior optic lobe (Chang, 2001).

Loss of hh results in a strong reduction of the head midline epidermis, a reduction in the size of the brain and optic lobe, and the total absence of the larval and adult eye primordium. Temperature-sensitive shift experiments of hh^ts2 embryos indicate that the phenocritical period for Hh function in Bolwig's organ development is between 4 and 7 hours. Aside from the larval eye, the primordium of the compound eye, which is marked from stage 12 onward by the expression of eyeless (ey), is also affected by the loss of hh. Heatshock induced overexpression of hh, as well as loss of ptc, causes an increase in larval eye neurons and optic lobe precursors. Interestingly, ectopic Hh activity is able to induce optic lobe and Bolwig's organ tissue in the head midline and thereby generate a cyclops phenotype similar to the condition described above for partial reduction of dpp. Applying heatshocks at different times of development indicates that the phenocritical period for the Hh induced cyclops is early, between 2.5 and 5 hours. Thus, heat pulses administered during this time cause fusion of the optic lobe and, at a lower frequency, of the larval eye without significantly increasing the number of optic lobe and larval eye cells. By contrast, later heat pulses (after 5 hours) lead to larval eye/optic lobe hyperplasia but no concomitant cyclops phenotype (Chang, 2001).

The finding that both loss of Hh and Dpp cause the absence of visual structures, and ectopic expression of Hh and partial loss of Dpp cause transformation of head midline epidermis into visual primordium, begs the question of how the two signaling pathways interact. In Drosophila compound eye development, hh expression is required to turn on dpp expression. To establish whether a regulatory relationship exists between Hh and Dpp signaling, the expression of dpp and pMAD was examined in the background of hh loss of function, as well as hh, ptc and Cubitus interruptus (Ci) expression in the background of dpp loss of function. Cells in which Dpp signaling is activated can be visualized by an antibody against phosphorylated MAD (pMAD) protein. Dpp RNA expression and pMAD are normal in a stage 5-9 hh-null background, indicating that Hh is not required to activate Dpp signaling in the embryonic head (Chang, 2001).

The expression of hh and ptc is normal in early embryos mutant for dpp. Since ptc is a downstream target of Hh signaling, this result strongly suggests that Dpp signaling is not required to activate the Hh cascade. To show more directly whether this cascade is interrupted, the antibody AbN, which recognizes both the full-length Ci protein and the cleaved repressor form (Ci75) was used in the background of a dpp-null mutation. According to the present model, Hh function consists of preventing the cleavage of the Ci protein to generate the repressor form, which is able to enter the nucleus and inhibit transcription of target genes such as ato and/or hh. In a mutation of Ci that produces only the repressor form or in eye clones that lack hh, a higher level of Ci can be detected in the cells. In dpp-null embryos, cytoplasmic Ci signal in the visual primordium of stage 7 embryos is at the same level as in wild type, indicating that Dpp is not required for Hh signal to go through. However, it should be conceded that it is very difficult to quantify, in embryonic tissues as opposed to cultured cells, expression levels using the Ci antibodies available, which leaves open the possibility that Dpp might have a quantitative effect of on the strength of the Hh signal reaching the nucleus (Chang, 2001).

Taken together, these findings suggest that no direct interaction exists between Hh and Dpp signaling, and that the antagonistic effect of Hh and Dpp on the formation of visual structures is most probably based upon an indirect interaction between the two signaling pathways that involves the expression of the eye genes so and eya (Chang, 2001).

These results suggest that, similar to its expression in the trunk, Dpp forms a gradient that traverses the anterior brain/eye field from dorsal to ventral. In the trunk, Dpp is restricted by the maternal morphogen Dorsal to the dorsal half of the embryo. Ventrally, the Dorsal morphogen turns on the Chordin homolog sog, as well as a transcriptional repressor of Dpp-activated genes, brinker (brk). Highest levels of Dpp at a mid-dorsal level turn on or stabilize target genes such as zen, which commit cells to amnioserosa fate. Moderate Dpp levels activate pannier and other targets that specify dorsolateral fates (non-neural epidermis, tracheae). A second BMP homolog, Screw, is required with Dpp for mid-dorsal fates. The activity of sog and brk inhibits Dpp and Screw in the ventral ectoderm, thereby allowing the expression of proneural genes and the subsequent neuralization in this domain. Paradoxically, Sog potentiates Dpp function mid-dorsally (Chang, 2001).

In the head region, highest levels of Dpp are required to promote mid dorsal fates (head epidermis, analogous to amnioserosa in the trunk). The activation of screw is involved in this process, similar to its role in the dorsomedial trunk. Intermediate Dpp levels promote dorsolateral fates (visual primordium). Low levels of Dpp are reached in the protocerebral neurectoderm and are permissive for the formation of protocerebral neuroblasts. Several of the regulatory genes expressed in the anterior brain and eye field may be direct targets of Dpp signaling. The findings show that so, eya and omb are activated by Dpp in the visual primordium. These regulatory genes initiate the fate of visual structures, in particular larval eye and outer optic lobe. It has recently been shown that eya and so are also targets of Dpp signaling in the eye imaginal disc (Chang, 2001).

The secondary restriction of so (and other genes with bilateral expression domains developing from unpaired domains, including tll and otd) is effected by the Dpp target zen in the dorsal midline. This homeobox gene is expressed as a response to peak levels of Dpp in the dorsal midline, including amnioserosa and, in the head of the embryo, in the dorsomedial head epidermis primordium. Loss of zen, similar to reduction of Dpp, results in the absence of amnioserosa and head epidermis, and a cyclops phenotype (Chang, 2001).

Hh is positively required for the visual system. Loss of this gene causes the absence of the larval eye, as well as the adult eye primordium. This phenotype is reminiscent of the later requirement of Hh for the initiation of cell differentiation in the larval eye imaginal disc. Increased expression of Hh, as well as absence of the inhibitor of Hh function, Ptc, results in a cyclops phenotype (Chang, 2001).

In view of these results, it is speculated that the interaction between Dpp and Hh is indirect and requires the function of so, eya and possibly other 'early eye genes' -- according to this model, Dpp activates so and eya in the eye field. Slightly later, expression of so and eya is lost dorsomedially, due to repression by Zen at this level. In a second step, the expression of Hh (which comes on later than Dpp) triggers larval eye fate in cells close to the Hh source. The response of a cell to Hh, that is, its expression of ato, depends on its previously expressing so and eya. Finally, Ptc inhibits the range of Hh action, similar to its alleged function in the trunk and imaginal discs (Chang, 2001).

A model is proposed to explain the phenotypes resulting from manipulating Dpp, Hh and Ptc expression:

1. In wild type, Hh can activate larval eye only in cells expressing so and eya. No larval eye develops in the dorsal midline because so is down regulated in this region rapidly, and Hh 'has no opportunity' to overcome the ptc mediated inhibition and induce visual system at an early stage when so is still present in the dorsal midline (Chang, 2001).
2. In ptc^-, Hh is able to induce larval eye fate in the dorsal midline because it is not inhibited at the early stage when so is still expressed dorsomedially (Chang, 2001).
3. Heatshock-induced Hh expression at an early stage (stage 5; around 3 hours) has the same effect, overcoming the ptc-mediated inhibition and inducing larval eye dorsomedially (Chang, 2001).
4. If the level of Dpp is reduced (in dpp null heterozygote, or dpp hypomorph), so and eya are stably expressed in the dorsal midline, since zen, which normally inhibits the early eye genes, is not expressed. As a result Hh can induce larval eye dorsomedially (Chang, 2001).
5. In the cyclops phenotype that results from reduction of Dpp, the visual primordium develops as a double crested placode that spans the dorsal midline. In this placode, the posterior crest is formed by larval eye cells, in line with the tenet that Hh induces larval eye fate in the cells next to the Hh source (posteriorly). The anterior crest, which is further away from the Hh source, constitutes posterior optic lobe (Chang, 2001).
6. In the cyclops phenotype induced by loss of Ptc or overexpression of Hh, larval eye cells are increased in number, compared with the Dpp reduction induced cyclops. At the same time, posterior optic lobe cells are reduced in number (Chang, 2001).

The topology in which different derivatives of the anterior brain anlage are laid out in the early embryo exhibits considerable similarity to that of vertebrates. To appreciate this similarity, one needs to remember that the neurectoderm of insects does not invaginate. As a result, early embryonic tissues located in the dorsal midline (i.e. the head midline ectoderm) of the fly embryo remain where they are, i.e. mid-dorsally, whereas in vertebrates, they form the ventral midline of the neural tube. This inverse topology may explain in part why dorsomedial structures in Drosophila share several functional and molecular similarities with the ventral forebrain in vertebrates. For example, both give rise to neuroendocrine centers (the pars intercerebralis of the insect brain, hypothalamus of vertebrates). In both vertebrates and insects, cells that start out as epithelial placodes in the foregut anlage anteriorly adjacent to the eye field, form neurohemal structures (anterior pituitary in vertebrates, corpora cardiaca in insects) that become innervated by the neuroendocrine neurons derived from the midventral/mid-dorsal brain. The topological similarity between the eye field in Drosophila and vertebrates extends to the location of the eye. In both systems, the eye maps close to the midline and genetic manipulations affecting the midline result in the fusion of the eyes (cyclopia) (Chang, 2001).

The dorsal location of the eye field and protocerebral neurectoderm in Drosophila, as well as all extant arthropods, is not easy to reconcile with the hypothesis that the chordate body plan is derived from an arthropod/annelid-like ancestor whose dorsoventral axis is reversed, although it does not directly contradict this idea. Thus, eye field and protocerebral ectoderm of ancestral arthropods might have actually occupied a ventral position in front of the stomodeum, and subsequently shifted dorsally. However, given that no comparative-structural or fossil evidence exists for such a shift, an alternative hypothesis can be offered: the CNS of the ancestor of chordates (deuterostomes) and arthropods/annelids (protostomes) may have been restricted to the head of the animal where also sensory receptors (eyes, statocysts, chemoreceptors) are concentrated. In support of this view, nerve cells in many groups of platyhelminths, in particular Acoels (considered as the sister group of bilaterians according to recent molecular-phylogeneitc data), are exclusively derived from the anterior pole of the embryo. From this primitive anterior ganglion of the bilaterian ancestor, the protocerebrum/eye field of present day bilaterians is directly derived, with no change in dorsoventral axis. In the trunk region, which originally lacked central neurons, a central nervous system was 'added' that followed different patterns during evolution. In the line leading to higher protostomes, ganglia located ventrally were added, whereas a dorsal trunk neurectoderm formed in chordates (Chang, 2001).

Irrespective of which of the two aforementioned hypotheses regarding topology of the neural fate map will turn out to be correct, the high degree of conservation of signaling pathways and regulatory genes controlling the patterning of the fate map in Drosophila and vertebrates emphasizes how 'close' the body plans manifested during early embryogenesis still are. Dpp/BMP and Hh/Shh signaling are centrally involved in head patterning in both systems, and could have exerted this role already in the bilaterian ancestor. However, it is also true that the impact of Dpp and Hh signaling on midline and eye structures seems very different in chordates and arthropods, which makes the independent recruitment of the two signaling pathways into head patterning in these phyla a distinct possibility. In chordates, loss of Hh results in a cyclops phenotype and holoprosencephaly, since high levels of Hh are required for hypothalamus and optic stalk. Hh positively regulates Pax2, a regulatory gene expressed in and required for the optic stalk. In the Drosophila embryo, excess function of Hh causes cyclopia. Moreover, Hh has a positive effect on the Pax6 homolog, eyeless; ey expression requires the presence of the Hh signal (Chang, 2001).

The effect of BMPs/Dpp on early eye formation maybe more similar than the role of Shh/Hh signaling. In Drosophila, both at the early embryonic and larval stage, Dpp promotes eye formation and differentiation. Vertebrate BMPs are expressed in the dorsal neural tube and are required for dorsal cell fates in the spinal cord, brain and eye. In mouse, BMP2, BMP4, BMP5, BMP6, BMP6 and BMP7 are expressed in the dorsal telencephalon, a region that gives rise to the choroid plexus and dorsomedial walls of the cerebral cortex (hippocampus) and diencephalon. At a later stage, BMP7 is also expressed in the retina. Mice homozygous for BMP2 and BMP4 die long before fate changes in the forebrain can be scored. BMP7 homozygotes show a late embryonic phenotype that includes degeneration of the retina (Chang, 2001).

When comparing the expression pattern of conserved regulatory genes, such as otd, tll, so and many others in anterior brain and eye development of fruit flies and vertebrates, one is also struck by the high number of similarities. These similarities indicate that the bilaterian ancestor might have possessed a head in which photoreceptors, various brain structures and neuroendocrine cells were laid out in a way reminiscent of the pattern found in present day taxa. This obviously does not imply the existence of complex organs, such as the eye, pituitary or brain structures. What it does imply is that the bilaterian ancestor had an anterior ‘neurectoderm’ in which clusters of cells with the basic properties of photoreceptors, pigment cells, neuroendocrine cells or central neurons were positioned in a pattern reminiscent of the modern pattern formed by the progenitors of these structures in different animals. During evolution, these cell types diversified further and became shaped by morphogenetic movements into more complex organs. For example, in the chordates (including urochordates and cephalochordates), the anterior neurectoderm invaginated to form a tube that included all cells with the fate of photoreceptors, pigment cells and target neurons. In vertebrates these cells then evaginated as the optic cup, induced lens and other structures from the outer ectoderm and formed an eye. In the evolutionary line leading to arthropods, cells with the fate of photoreceptors and pigment cells were separated at an early developmental stage from cells destined to become optic target neurons. The former remained in the outer ectoderm and became organized into a compound eye, while the latter delaminated along with other neural stem cells to form the brain. The stage is set for comparative studies of eye morphogenesis and gene expression that will elucidate in more detail how a simple visual system changed into the various types of eyes that can be observed in extant animal groups (Chang, 2001).

References

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Gallitano-Mendel, A. and Finkelstein, R. (1997). Novel segment polarity gene interactions during embryonic head development in Drosophila. Dev. Biol. 192(2): 599-613

Mohler, J., Mahaffey, J.W., Deutsch, E., and Vani, K. (1995). Control of Drosophila head segment identity by the bZIP homeotic gene cnc. Development 121: 237-247

Rogers, B. T. and Kaufman, T. C. (1996). Structure of the insect head as revealed by the EN protein pattern in developing embryos. Development 122, 3419-3432

Nassif, C., et al. (1998). The role of morphogenetic cell death during Drosophila embryonic head development. Dev. Biol. 197(2): 170-186

Royet, J. and Finkelstein, F. (1995). Pattern formation in Drosophila head development: the role of the orthodenticle homeobox gene. Development 121: 3561-72

Schmidt-Ott, U. and Technau, G.M. (1993). Expression of en and wg in the embryonic head and brain of Drosophila indicates a refolded band of seven segment remnants. Development 116: 111-125

Genes involved in organ development

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