The Transcription Factor Optomotor-Blind Antagonizes Drosophila Haltere Growth by Repressing Decapentaplegic and Hedgehog Targets

In Drosophila, decapentaplegic, which codes for a secreted signaling molecule, is activated by the Hedgehog signaling pathway at the anteroposterior compartment border of the two dorsal primordia; the wing and the haltere imaginal discs. In the wing disc, Decapentaplegic and Hedgehog signaling targets are implicated in cell proliferation and cell survival. However, most of their known targets in the wing disc are not expressed in the haltere disc due to their repression by the Hox gene Ultrabithorax. The T-box gene optomotor-blind escapes this repression in the haltere disc, and therefore is expressed in both the haltere and wing discs. Optomotor-blind is a major player during wing development and its function has been intensely investigated in this tissue, however, its role in haltere development has not been reported so far. Here we show that Optomotor-blind function in the haltere disc differs from that in the wing disc. Unlike its role in the wing, Optomotor-blind does not prevent apoptosis in the haltere but rather limits growth by repressing several Decapentaplegic and Hedgehog targets involved both in wing proliferation and in modulating the spread of morphogens similar to Ultrabithorax function but without disturbing Ultrabithorax expression.     

Morphogens and endocytosis

During development, secreted signaling proteins of the Wingless/Wnt, Hedgehog and Decapentaplegic (Dpp)/Bone Morphogenic Protein (BMP) families act as morphogens. Previous work had shown that these molecules act directly on distant cells, although until recently nothing was known about how they reach those distant cells. During the past two years, work carried out on Drosophila using genetic and cell biology approaches have revealed that endocytosis plays a central part in the mechanisms that control the spread of morphogens.     

The role of Wingless signaling in establishing the anteroposterior and dorsoventral axes of the eye disc

The posteriorly expressed signaling molecules Hedgehog and Decapentaplegic drive photoreceptor differentiation in the Drosophila eye disc, while at the anterior lateral margins Wingless expression blocks ectopic differentiation. We show here that mutations in axin prevent photoreceptor differentiation and lead to tissue overgrowth and that both these effects are due to ectopic activation of the Wingless pathway. In addition, ectopic Wingless signaling causes posterior cells to take on an anterior identity, reorienting the direction of morphogenetic furrow progression in neighboring wild-type cells. We also show that signaling by Decapentaplegic and Hedgehog normally blocks the posterior expression of anterior markers such as Eyeless. Wingless signaling is not required to maintain anterior Eyeless expression and in combination with Decapentaplegic signaling can promote its downregulation, suggesting that additional molecules contribute to anterior identity. Along the dorsoventral axis of the eye disc, Wingless signaling is sufficient to promote dorsal expression of the Iroquois gene mirror, even in the absence of the upstream factor pannier. However, Wingless signaling does not lead to ventral mirror expression, implying the existence of ventral repressors.     

器官成形素调控果蝇翅芽细胞形貌的研究进展

果蝇翅芽是研究细胞形貌发生的模式系统。在果蝇翅芽的发育过程中,器官成形素由浓度高的区域(成形素表达细胞)向浓度低的区域(接收细胞)移动,形成动态的浓度梯度。器官成形素信号通路的激活调控翅芽细胞的形貌发生、存活、生长和分化。目前已鉴定的在翅芽细胞表达的器官成形素包括Hedgehog(Hh),Decapentaplegic(Dpp)和Wingless(Wg)。结合国际最新研究进展,本文综述了3种器官成形素在翅芽细胞形貌发生过程中的重要作用,讨论了细胞形貌发生的分子机制。     

Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells

Using K14deltaNbeta-cateninER transgenic mice, we show that short-term, low-level beta-catenin activation stimulates de novo hair follicle formation from sebaceous glands and interfollicular epidermis, while only sustained, high-level activation induces new follicles from preexisting follicles. The Hedgehog pathway is upregulated by beta-catenin activation, and inhibition of Hedgehog signaling converts the low beta-catenin phenotype to wild-type epidermis and the high phenotype to low. beta-catenin-induced follicles contain clonogenic keratinocytes that express bulge markers; the follicles induce dermal papillae and provide a niche for melanocytes, and they undergo 4OHT-dependent cycles of growth and regression. New follicles induced in interfollicular epidermis are derived from that cellular compartment and not through bulge stem cell migration or division. These results demonstrate the remarkable capacity of adult epidermis to be reprogrammed by titrating beta-catenin and Hedgehog signal strength and establish that cells from interfollicular epidermis can acquire certain characteristics of bulge stem cells.     

Novel brain wiring functions for classical morphogens: a role as graded positional cues in axon guidance

During embryonic development, morphogens act as graded positional cues to dictate cell fate specification and tissue patterning. Recent findings indicate that morphogen gradients also serve to guide axonal pathfinding during development of the nervous system. These findings challenge our previous notions about morphogens and axon guidance molecules, and suggest that these proteins, rather than having sharply divergent functions, act more globally to provide graded positional information that can be interpreted by responding cells either to specify cell fate or to direct axonal pathfinding. This review presents the roles identified for members of three prominent morphogen families--the Hedgehog, Wnt and TGFbeta/BMP families--in axon guidance, and discusses potential implications for the molecular mechanisms underlying their guidance functions.     

Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs

Hedgehog (HH) and Decapentaplegic (DPP) direct anteroposterior patterning in the developing Drosophila wing by functioning as short- and long-range morphogens, respectively. Here, we show that the activity of DPP is graded and is directly regulated by a novel HH-dependent mechanism. DPP activity was monitored by visualizing the activated form of Mothers against dpp (MAD), a cytoplasmic transducer of DPP signaling. We found that activated MAD levels are highest near the source of DPP but are unexpectedly low in the cells that express dpp. HH induces dpp in these cells; it also attenuates their response to DPP by downregulating expression of the DPP receptor thick veins (tkv). We suggest that regulation of tkv by HH is a key part of the mechanism that controls the level and distribution of DPP.     

Elaboration and ultrastructural changes in the pore canal system of the mineralized cuticle of Carcinus maenas during the moulting cycle

Two basic structural components are concerned in the elaboration of the pore canal system in the mineralized cuticle of the decapod crab Carcinus maenas: tubular cytoplasmic extensions originating from epidermis and vertical fibres. These components are present from the moment the first procuticular materials of the new cuticle are laid down but their organization varies according to a precise schedule during the further moult cycle stages. Cytoplasmic extensions form a complicated branching system connecting the epidermal layer with all regions of the cullcular compartment, at least transitorily. During the moult cycle the prolongation of this cellular system appears to result from two concomitant but opposite phenomena. Before ecdysis the growth of cell extensions in the proximal cuticular layers prevails over their regression at the distal level. During the post-moult period these phenomena are reversed in importance so that the pore canal system is without cytoplasmic material as soon as intermoult starts. The depositing of vertical fibres takes place in close contact with the proximal cell extension plasma membrane, which never bears dense plaques. As moult stages progress, they are gradually organized into twisted sheaths that persist throughout the intermoult. Incidentally, some fibres invade the pore canal lumen freed from cell extensions. Some aspects regarding the fine organization, the chemical composition and the functional significance of both epidermal tubular extensions or vertical fibres are also discussed in the light of previous investigations carried out on crustaceans and in other arthropods.     

The EGF receptor and notch signaling pathways control the initiation of the morphogenetic furrow during Drosophila eye development

The onset of pattern formation in the developing Drosophila retina begins with the initiation of the morphogenetic furrow, the leading edge of a wave of retinal development that transforms a uniform epithelium, the eye imaginal disc into a near crystalline array of ommatidial elements. The initiation of this wave of morphogenesis is under the control of the secreted morphogens Hedgehog (Hh), Decapentaplegic (Dpp) and Wingless (Wg). We show that the Epidermal Growth Factor Receptor and Notch signaling cascades are crucial components that are also required to initiate retinal development. We also show that the initiation of the morphogenetic furrow is the sum of two genetically separable processes: (1) the 'birth' of pattern formation at the posterior margin of the eye imaginal disc; and (2) the subsequent 'reincarnation' of retinal development across the epithelium.     

The Decapentaplegic morphogen gradient: a precise definition

Two key processes are in the basis of morphogenesis: the spatial allocation of cell types in fields of na?ve cells and the regulation of growth. Both are controlled by morphogens, which activate target genes in the growing tissue in a concentration-dependent manner. Thus the morphogen model is an intrinsically quantitative concept. However, quantitative studies were performed only in recent years on two morphogens: Bicoid and Decapentaplegic. This review covers quantitative aspects of the formation and precision of the Decapentaplegic morphogen gradient. The morphogen gradient concept is transitioning from a soft definition to a precise idea of what the gradient could really do.     

Heparan sulphate proteoglycans: the sweet side of development

Pattern formation during development is controlled to a great extent by a small number of conserved signal transduction pathways that are activated by extracellular ligands such as Hedgehog, Wingless or Decapentaplegic. Genetic experiments have identified heparan sulphate proteoglycans (HSPGs) as important regulators of the tissue distribution of these extracellular signalling molecules. Several recent reports provide important new insights into the mechanisms by which HSPGs function during development.     

A novel interaction between hedgehog and Notch promotes proliferation at the anterior-posterior organizer of the Drosophila wing

Notch has multiple roles in the development of the Drosophila melanogaster wing imaginal disc. It helps specify the dorsal-ventral compartment border, and it is needed for the wing margin, veins, and sensory organs. Here we present evidence for a new role: stimulating growth in response to Hedgehog. We show that Notch signaling is activated in the cells of the anterior-posterior organizer that produce the region between wing veins 3 and 4, and we describe strong genetic interactions between the gene that encodes the Hedgehog pathway activator Smoothened and the Notch pathway genes Notch, presenilin, and Suppressor of Hairless and the Enhancer of split complex. This work thus reveals a novel collaboration by the Hedgehog and Notch pathways that regulates proliferation in the 3-4 intervein region independently of Decapentaplegic.     

Regulating mechanical tension at compartment boundaries in Drosophila

During animal development, cells with similar function and fate often stay together and sort out from cells with different fates. In Drosophila wing imaginal discs, cells of anterior and posterior fates are separated by a straight compartment boundary. Separation of anterior and posterior cells requires the homeodomain-containing protein Engrailed, which is expressed in posterior cells. Engrailed induces the expression of the short-range signaling molecule Hedgehog in posterior cells and confines Hedgehog signal transduction to anterior cells. Transduction of the Hedgehog signal in anterior cells is required for the separation of anterior and posterior cells. Previous work showed that this separation of cells involves a local increase in mechanical tension at cell junctions along the compartment boundary. However, how mechanical tension was locally increased along the compartment boundary remained unknown. A recent paper now shows that the difference in Hedgehog signal transduction between anterior and posterior cells is necessary and sufficient to increase mechanical tension. The local increase in mechanical tension biases junctional rearrangements during cell intercalations to maintain the straight shape of the compartment boundary. These data highlight how developmental signals can generate patterns of mechanical tension important for tissue organization.     

How the growth cone recognizes and responds to its environment

Four interactive processes—adhesion, guidance, migration and growth—combine to direct the axonal growth cone to its targets. It is becoming clear that the sensors of the external environment, the axonal receptors and adhesion molecules, activate second messenger systems in the growth cone. This allows a cytoplasmic integration of guidance signals acting upon the growth cone, that feeds back upon the adhesion molecules and the cytoskeleton to select the direction of growth. Movement is primarily generated by the actin microfilaments, growth is dependent upon the microtubules. This review examines the interdependence of these processes during the initial phase of axon elongation, using examples from insects to mammals.     

The hedgehog morphogen and gradients of cell affinity in the abdomen of Drosophila

The adult abdomen of Drosophila is a chain of anterior (A) and posterior (P) compartments. The engrailed gene is active in all P compartments and selects the P state. Hedgehog enters each A compartment across both its anterior and posterior edges; within A its concentration confers positional information. The A compartments are subdivided into an anterior and a posterior domain that each make different cell types in response to Hedgehog. We have studied the relationship between Hedgehog, engrailed and cell affinity. We made twin clones and measured the shape, size and displacement of the experimental clone, relative to its control twin. We varied the perceived level of Hedgehog in the experimental clone and find that, if this level is different from the surround, the clone fails to grow normally, rounds up and sometimes sorts out completely, becoming separated from the epithelium. Also, clones are displaced towards cells that are more like themselves: for example groups of cells in the middle of the A compartment that are persuaded to differentiate as if they were at the posterior limit of A, move posteriorly. Similarly, clones in the anterior domain of the A compartment that are forced to differentiate as if they were at the anterior limit of A, move anteriorly. Quantitation of these measures and the direction of displacement indicate that there is a U-shaped gradient of affinity in the A compartment that correlates with the U-shaped landscape of Hedgehog concentration. Since affinity changes are autonomous to the clone we believe that, normally, each cell's affinity is a direct response to Hedgehog. By removing engrailed in clones we show that A and P cells also differ in affinity from each other, in a manner that appears independent of Hedgehog. Within the P compartment we found some evidence for a U-shaped gradient of affinity, but this cannot be due to Hedgehog which does not act in the P compartment.     

Three Drosophila EXT genes shape morphogen gradients through synthesis of heparan sulfate proteoglycans

The signaling molecules Hedgehog (Hh), Decapentaplegic (Dpp) and Wingless (Wg) function as morphogens and organize wing patterning in Drosophila. In the screen for mutations that alter the morphogen activity, we identified novel mutants of two Drosophila genes, sister of tout-velu (sotv) and brother of tout-velu (botv), and new alleles of tout-velu (ttv). The encoded proteins of these genes belong to an EXT family of proteins that have or are closely related to glycosyltransferase activities required for biosynthesis of heparan sulfate proteoglycans (HSPGs). Mutation in any of these genes impaired biosynthesis of HSPGs in vivo, indicating that, despite their structural similarity, they are not redundant in the HSPG biosynthesis. Protein levels and signaling activities of Hh, Dpp and Wg were reduced in the cells mutant for any of these EXT genes to a various degree, Wg signaling being the least sensitive. Moreover, all three morphogens were accumulated in the front of EXT mutant cells, suggesting that these morphogens require HSPGs to move efficiently. In contrast to previous reports that ttv is involved exclusively in Hh signaling, we found that ttv mutations also affected Dpp and Wg. These data led us to conclude that each of three EXT genes studied contribute to Hh, Dpp and Wg morphogen signaling. We propose that HSPGs facilitate the spreading of morphogens and therefore, function to generate morphogen concentration gradients.