The Interactive Fly

Genes involved in tissue and organ development

Stomatogastric nervous system

  • What is the stomatogastric nervous system?
  • Tip cell-derived RTK signaling initiates cell movements in the Drosophila stomatogastric nervous system anlage
  • Anatomy of the stomatogastric nervous system associated with the foregut in Drosophila melanogaster and Calliphora vicina third instar larvae
  • Genetic tools for the analysis of Drosophila stomatogastric nervous system development
    Genes expressed in the stomatogastric nervous system

    What is the stomatogastric nervous system?

    The stomatogastric nervous system (SNS) consists of several peripheral ganglia that receive input from the brain; these ganglia in turn innervate muscles, pharynx, and gut. Precursors originate from the primordium of the foregut or stomodeum [Images]. The SNS is considered to be derived from the labral segment, the most anterior of the head segments. Early in development several subsets of precursors delaminate from the stomodeal epithelium as individual cells.

    Three cells are singled out from within a single proneural cluster, known as the SNS anlage; these cells then initiate a distinct feature of SNS development. Serving as tip cells, they direct a second phase of SNS development wherein an invagination process occurs, forming three distinct epithelial folds with a single proneural-expressing cell at each tip. achaete-scute and neurogenic genes function here in the same manner as they do in the development of the ventral nerve cord, except that three cells are selected, not just one. The homeobox protein Goosecoid marks cells fated to become SNS cells.

    Once the invagination process is complete, proneural gene expression appears de novo in all cells contained within the three invaginations; the three invaginations then pinch off from the epithelium to form separate epithelial vesicles. At later stages the cells of the three vesicles migrate to various locations where they differentiate as neurons, organizing into the mature embryonic SNS. Subsequently, these neural cells generate the axonal scaffold. Neurons from the individual ganglia send out pioneer axons that meet up with outgrowing axons from the other ganglia and eventually establish the interconnecting nerves. Other neurons send out axons to establish the nerves that innervate the dorsal pharyngeal muscles, the midgut and the CNS.

    The mature embryonic SNS consists of only four ganglia (the frontal ganglion, the esophageal ganglion 1, the esophageal ganglion 2, and the proventricular ganglion) and their associated nerve tracts. The glia of the mature SNS are found as three groups of cells: one group is associated with the frontal ganglion (the frontal ganglion glia), a second group is found in the frontal commissure, at the base of the frontal nerve (commisural glia), and a third group is located at the fork in the recurrent nerve, off of which the two esophageal ganglia extend (esophageal ganglia glia).

    Tip cell-derived RTK signaling initiates cell movements in the Drosophila stomatogastric nervous system anlage

    The stomatogastric nervous system (SNS) of Drosophila is a simply organized neural circuitry that innervates the anterior enteric system. Unlike the central and the peripheral nervous systems, the SNS derives from a compact epithelial anlage in which three invagination centers, each giving rise to an invagination fold headed by a tip cell, are generated. Tip cell selection involves lateral inhibition, a process in which Wingless (Wg) activity adjusts the range of Notch signaling. RTK signaling mediated by the Epidermal growth factor receptor plays a key role in two consecutive steps during early SNS development. Like Wg, Egfr signaling participates in adjusting the range of Notch-dependent lateral inhibition during tip cell selection. Subsequently, tip cells secrete the Egfr ligand Spitz and trigger local RTK signaling, which initiates morphogenetic movements resulting in the tip cell-directed invaginations within the SNS anlage (González-Gaitán, 2000).

    In order to investigate the role of RTK signaling in SNS development, lack-of-function mutants of the Egfr ligand Spitz were examined. In spitz mutants, the formation of the four SNS ganglia is strongly impaired. The SNS anlage, however, forms normally. In addition, the expression domain of wg and proneural AS-C genes is indistinguishable from a wild-type SNS anlage. At the stage when the three ac-expressing cells were singled-out within the wild-type SNS anlage, only one ac positive cell is found in spitz mutants. The same phenotype has been observed in wg mutants or mutants lacking an integral component of the wg pathway. Since no altered wg pattern was found in the spitz mutant SNS anlage, Spitz-dependent RTK signaling may act in parallel or in combination with wg to adjust the proper range of Notch-dependent lateral inhibition. In contrast to wg mutants, however, no invagination fold is observed. This observation indicates that the singled-out ac-expressing cell of spitz mutants has lost the ability to function as a tip cell and possibly fails to induce morphogenetic movements within the SNS anlage (González-Gaitán, 2000).

    spitz, like other genes encoding components of the Egfr signaling pathway such as Egfr, Ras, Raf and the cascade of MAP kinases, is ubiquitously expressed. Local activation of Egfr signaling requires the transmembrane protein Star, which is necessary for the secretion of Spitz. Star is expressed in restricted patterns corresponding to the Spitz secreting cells. In the SNS anlage, it was noted that Star becomes restricted to the three tip cells and is maintained in these cells when invagination takes place. As in spitz mutants, the Star mutant SNS anlage is established normally; only one ac-expressing cell is selected and no invagination occurs. Consistently, Star mutants fail to develop the proper set of SNS ganglia and the associated nerves. These observations suggest that tip cells are a Star-dependent source of Spitz activity that triggers Egfr-dependent RTK signaling in the neighboring cells within the SNS anlage. This conclusion is supported by the finding that phosphorylated MAPK, a cellular marker for RTK signaling activity, is indeed activated in cells of the invagination folds, whereas phosphorylated MAPK does not appear in the Star mutant or in the spitz mutant SNS anlage (González-Gaitán, 2000).

    To examine whether activated Spitz is sufficient to induce cell movements within the SNS anlage, use was made of the GAL4/UAS system to misexpress secreted Spitz in an ectopic pattern. This was achieved through the expression of activated Spitz from a UAS promotor driven transgenethat was activated by Gal4 under the control of the actin promotor. Under the conditions applied, scattered UAS-dependent transgene expression is observed throughout the early embryo, including the SNS anlage. When activated Spitz is expressed in such a pattern, a variable number of supernumerary infoldings within the SNS anlagen are observed, indicating that activated Spitz is sufficient to initiate cell movements. This result, in conjunction with the observation that the invaginated cells express phosphorylated MAPK, provides evidence that tip cell-derived activated Spitz triggers RTK signaling to initiate the invagination process. This proposal was tested by blocking Egfr signaling in the anterior most region of the SNS anlage that gives rise to the first invagination fold. For this, a GAL4 driver (SNS1-Gal4) was used that causes UAS-dependent gene expression in the corresponding region of the SNS anlage. SNS1-Gal4-mediated expression of a dominant-negative Egfr mutant form from a UAS-controlled transgene causes a specific suppression of the anterior most invagination fold without affecting the others (González-Gaitán, 2000).

    The results demonstrate that RTK signaling participates in the selection of tip-cell-dependent invagination centers in the SNS anlage and is subsequently required to initiate morphogenetic movements resulting in invagination folds. This study does not focus on how RTK signaling ties into the wg-modulated Notch signaling process previously shown to be necessary for the selection of the three SNS invagination centers. The data indicate, however, that RTK signaling acts either in parallel or in combination with wg signaling to adjust the proper range of Notch-dependent lateral inhibition. Although in both wg and Egfr signaling mutants, only one ac-expressing cell is singled-out, the selected cells differ with respect to whether they function as tip cells or not. In wg mutants, the single cell causes an invagination, whereas in Egfr signaling mutants, the selected cell fails to provide this feature of SNS invagination centers. The results, therefore, consistently argue that tip cell-derived Spitz triggers local RTK signaling and thereby initiates the formation of invagination folds each headed by the Spitz-secreting tip cell. Thus, Egfr-dependent RTK signaling in Drosophila does not only participate in cell fate decisions and cell proliferation, but also triggers morphogenetic movements within an epithelium, as has been recently demonstrated for fibroblast growth factor (FGF) signaling. It will be interesting to see whether the role of the EGF pathway in cell migration differs at the cellular level from cell migration events triggered by activated FGF receptors (González-Gaitán, 2000).

    Anatomy of the stomatogastric nervous system associated with the foregut in Drosophila melanogaster and Calliphora vicina third instar larvae

    The stomatogastric nervous system (SNS) associated with the foregut was studied in 3rd instar larvae of Drosophila melanogaster and Calliphora vicina (blowfly). In both species, the foregut comprises pharynx, esophagus, and proventriculus. Only in Calliphora does the esophagus form a crop. The position of nerves and neurons was investigated with neuronal tracers in both species and GFP expression in Drosophila. The SNS is nearly identical in both species. Neurons are located in the proventricular and the hypocerebral ganglion (HCG), which are connected to each other by the proventricular nerve. Motor neurons for pharyngeal muscles are located in the brain not, as in other insect groups, in the frontal ganglion. The position of the frontal ganglion is taken by a nerve junction devoid of neurons. The junction is composed of four nerves: the frontal connectives that fuse with the antennal nerves (ANs), the frontal nerve innervating the cibarial dilator muscles and the recurrent nerve that innervates the esophagus and projects to the HCG. Differences in the SNS are restricted to a crop nerve only present in Calliphora and an esophageal ganglion that only exists in Drosophila. The ganglia of the dorsal organs give rise to the ANs, which project to the brain. The extensive conformity of the SNS of both species suggests functional parallels. Future electrophysiological studies of the motor circuits in the SNS of Drosophila will profit from parallel studies of the homologous but more accessible structures in Calliphora (Spoess, 2008).

    Genetic tools for the analysis of Drosophila stomatogastric nervous system development

    The Drosophila stomatogastric nervous system (SNS) is a compact collection of neurons that arises from the migration of neural precursors. This study describes genetic tools allowing functional analysis of the SNS during the migratory phase of development. GAL4 lines driven by fragments of the Ret promoter are described that yielded expression in a subset of migrating neural SNS precursors and also included a distinct set of midgut associated cells. Screening of additional GAL4 lines driven by fragments of the Gfrl/Munin, forkhead, twist and goosecoid (Gsc) promoters identified a Gsc fragment with expression from initial selection of SNS precursors until the end of embryogenesis. Inhibition of EGFR signaling using three identified lines disrupted the correct patterning of the frontal and recurrent nerves. To manipulate the environment traveled by SNS precursors, a FasII-GAL4 line with strong expression throughout the entire intestinal tract was identified. The transgenic lines described offer the ability to specifically manipulate the migration of SNS precursors and will allow the modeling and in-depth analysis of neuronal migration in ENS disorders such as Hirschsprung's disease (Hernandez, 2015).


    Forjanic, J. P., et al. (1997). Genetic analysis of stomatogastric nervous system development in Drosophila using enhancer trap lines. Development 186: 139-154. PubMed ID: 9205135

    González-Gaitan, M. and Jäckle, H. (1995). Invagination centers within the Drosophila stomatogastric nervous system anlage are positioned by Notch-mediated signaling which is spatially controlled through wingless. Development 121: 2313-25. PubMed ID: 7671798

    González-Gaitan, M. and Jäckle, H. (2000). Tip cell-derived RTK signaling initiates cell movements in the Drosophila stomatogastric nervous system anlage. EMBO Reports 1: 366-371. PubMed ID: 11269504

    Goriely, A., et al. (1996). A functional homologue of goosecoid in Drosophila. Development 122: 1641-1650. PubMed ID: 8625850

    Hartenstein, V., Tepass, U. and Gruszynski-deFeo, E. (1996). Proneural and neurogenic genes control specification and morphogenesis of stomatogastric nerve cell precursors in Drosophila Dev. Biol. 173: 213-227. PubMed ID: 8575623

    Hernandez, K., Myers, L. G., Bowser, M. and Kidd, T. (2015). Genetic tools for the analysis of Drosophila stomatogastric nervous system development. PLoS One 10: e0128290. PubMed ID: 26053861

    Schmidt-Ott, et al. (1994). Number, identity, and sequence of the Drosophila head segments as revealed by neural elements and their deletion patterns in mutants. Proc. Natl. Acad. Sci. 91: 8363-8367. PubMed ID: 7915837

    Spiess, R., Schoofs, A. and Heinzel, H. G. (2008). Anatomy of the stomatogastric nervous system associated with the foregut in Drosophila melanogaster and Calliphora vicina third instar larvae. J. Morphol. 269(3): 272-82. PubMed ID: 17960761

    Genes involved in organ development

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