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Biomedical subjects

K Moses

Publications and source records attributed to K Moses.

At least 19 recordsLinked to original sources
PubMed2001

Perturbing nuclear transport in Drosophila eye imaginal discs causes specific cell adhesion and axon guidance defects.

To study nucleocytoplasmic transport during multicellular development, we developed a sensitive nuclear protein import assay in living blastoderm embryos. We show that dominant negative truncations of the human nuclear transport receptor karyopherinbeta/Importinbeta (DNImpbeta) disrupt mRNA export and protein import in Drosophila. To test the sensitivity of different developmental processes to nuclear trafficking perturbations, we expressed DNImpbeta behind the morphogenetic furrow of the eye disc, at a time when photoreceptors are patterned and project their axons to the brain. DNImpbeta expression does not disrupt the correct specification of different photoreceptors, but causes a defect in cell adhesion that leads to some photoreceptors descending below the layer of ommatidia. The photoreceptors initially project their axons correctly to the posterior, but later their axons are unable to enter the optic stalk en route to the brain and continue to project an extensive network of misguided axons. The axon guidance and cell adhesion defects are both due to a disruption in the function of Ketel, the Drosophila ortholog of Importinbeta. We conclude that cell adhesion and axon guidance in the eye have specific requirements for nucleocytoplasmic transport, despite involving processes that occur primarily at the cell surface.

Active Transport, Cell Nucleus↗
PubMed2001

Extraperitoneal laparoscopic hernia repair with local anesthesia.

BACKGROUND: This review aimed to compare laparoscopic preperitoneal herniorrhaphy (LPPH) using a laryngeal mask airway and local anesthesia with conventional open herniorrhaphy using similar anesthetic conditions. METHODS: A retrospective review of 238 hernia operations was conducted from October 1996 through September 1998. Laparoscopic preperitoneal hernia repairs with the patient under laryngeal mask airway anesthesia were performed initially using 10 ml of 0.5% bupivacaine (LPPH+10 group). This was compared with hernia repair using 30 ml of 0.5% bupivacaine (LPPH+30 group). Both LPPH groups were compared with a plug and patch "Gilbert" hernia repair group. Postoperative pain was compared in the recovery room and outpatient suite. RESULTS: The LPPH+30 group required significantly less postoperative pain medication than the LPPH+10 group. The LPPH+30 group required slightly more pain medication in the recovery room than the open hernia repair group, but in the postanesthesia care unit (PACU) unit, the LPPH+30 group used less pain medication. A similar number of LPPH+30 patients, and open hernia repair patients required no pain medication. CONCLUSIONS: The use of a long-acting local anesthetic, (30 ml of 0.5% bupivacaine via laryngeal mask airway) for laparoscopic preperitoneal hernia repair compared favorably with conventional open hernia repair using similar anesthetic techniques.

Analgesics, Opioid↗
PubMed2001

EGF receptor and Notch signaling act upstream of Eyeless/Pax6 to control eye specification.

The Drosophila compound eye is specified by the concerted action of seven nuclear factors that include Eyeless/Pax6. These factors have been called "master control" proteins because loss-of-function mutants lack eyes and ectopic expression can direct ectopic eye development. However, inactivation of these genes does not cause the presumptive eye to change identity. Surprisingly, we find that several of these eye specification genes are not coexpressed in the same embryonic cells-or even in the presumptive eye. We demonstrate that the EGF Receptor and Notch signaling pathways have homeotic functions that are genetically upstream of the eye specification genes, and show that specification occurs much later than previously thought-not during embryonic development but in the second larval stage.

Animal Structures↗
PubMed2001

Eye specification in Drosophila: perspectives and implications.

The discovery that Drosophila eyeless is homologous to vertebrate Pax6 produced enormous interest in eye specification and a reappraisal of eye evolution. While the transcription factor Eyeless/Pax6 is necessary and in some circumstances sufficient to induce eye development the simple story of eye specification has become more epic than haiku. At least seven other nuclear proteins act with Eyeless/Pax6 to induce the eye and, furthermore, extrinsic developmental signals are required. Some striking similarities between later events of retinal patterning in vertebrates and insects have led to a deeper debate on the evolutionary path to these apparently quite different organs.

Animals↗
PubMed2001

Expression of evolutionarily conserved eye specification genes during Drosophila embryogenesis.

Eye specification in Drosophila is thought be controlled by a set of seven nuclear factors that includes the Pax6 homolog, Eyeless. This group of genes is conserved throughout evolution and has been repeatedly recruited for eye specification. Several of these genes are expressed within the developing eyes of vertebrates and mutations in several mouse and human orthologs are the underlying causes of retinal disease syndromes. Ectopic expression in Drosophila of any one of these genes is capable of inducing retinal development, while loss-of-function mutations delete the developing eye. These nuclear factors comprise a complex regulatory network and it is thought that their combined activities are required for the formation of the eye. We examined the expression patterns of four eye specification genes, eyeless (ey), sine oculis (so), eyes absent (eya), and dachshund (dac) throughout all time points of embryogenesis and show that only eyeless is expressed within the embryonic eye anlagen. This is consistent with a recently proposed model in which the eye primordium acquires its competence to become retinal tissue over several time points of development. We also compare the expression of Ey with that of a putative antennal specifying gene Distal-less (Dll). The expression patterns described here are quite intriguing and raise the possibility that these genes have even earlier and wide ranging roles in establishing the head and visual field.

Animals↗
PubMed2001

Function of the Drosophila TGF-alpha homolog Spitz is controlled by Star and interacts directly with Star.

Drosophila Spitz is a homolog of transforming growth factor alpha (TGF-alpha) and is an activating ligand for the EGF receptor (Egfr). It has been shown that Star is required for Spitz activity. Here we show that Star is quantitatively limiting for Spitz production during eye development. We also show that Star and Spitz proteins colocalize in Spitz sending cells and that this association is not coincident with the site of translation--consistent with a function for Star in Spitz processing or transmission. Finally, we have defined minimal sequences within both Spitz and Star that mediate a direct interaction and show that this binding can occur in vivo.

Amino Acid Sequence↗
PubMed2001

Broad-complex, but not ecdysone receptor, is required for progression of the morphogenetic furrow in the Drosophila eye.

The progression of the morphogenetic furrow in the developing Drosophila eye is an early metamorphic, ecdysteroid-dependent event. Although Ecdysone receptor-encoded nuclear receptor isoforms are the only known ecdysteroid receptors, we show that the Ecdysone receptor gene is not required for furrow function. DHR78, which encodes another candidate ecdysteroid receptor, is also not required. In contrast, zinc finger-containing isoforms encoded by the early ecdysone response gene Broad-complex regulate furrow progression and photoreceptor specification. br-encoded Broad-complex subfunctions are required for furrow progression and proper R8 specification, and are antagonized by other subfunctions of Broad-complex. There is a switch from Broad complex Z2 to Z1 zinc-finger isoform expression at the furrow which requires Z2 expression and responds to Hedgehog signals. These results suggest that a novel hormone transduction hierarchy involving an uncharacterized receptor operates in the eye disc.

Animals↗
PubMed2001

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.

Animals↗
PubMed2000

Determination of Drosophila photoreceptors: timing is everything.

This review covers recent findings concerning the specification of the photoreceptor subtypes in the Drosophila eye. Particular attention is paid to aspects of retinal patterning and differentiation where relative timing of events seems to be tightly controlled and essential for proper assembly of the compound eye. For example, specification of the founding photoreceptors of each cluster requires sequential positive and negative signaling through the Notch pathway, and reiterated signaling through the epidermal growth factor receptor leads to the pairwise recruitment of the distinct types of photoreceptors in discrete zones across the eye. Results suggest that different signaling environments for these two receptors may exist across the disc, and that receiving cells may constantly shift their predisposition to respond to such signals by adopting given fates. In addition, considerable data exist that the rate of expansion of retinal patterning across the disc is restricted to allow the orderly patterning of retinal precursors, and that one mechanism for controlling this rate may be the co-ordinated expression anterior to the furrow of factors which both inhibit and promote the expansion of retinal patterning. Finally, this review considers the possibility that the morphogenetic furrow serves as a moving source of morphogens which supply spatial information to both anterior and posterior tissue, providing temporal cues that regulate the many events involved in orderly assembly of the precise array of retinal cell types in the compound eye.

Animals↗
PubMed1999

Genetics of epithelial polarity and pattern in the Drosophila retina.

This review is focused on recent advances in our understanding of the development of coordinated cell polarity, through experiments on the Drosophila compound eye. Each eye facet (or "ommatidium") contains a set of eight photoreceptor cells, placed so that their rhabdomeres form an asymmetric trapezoid. The array of ommatidia is organized so that these trapezoids are aligned in two mirror-image fields, dorsal and ventral to the eye midline (or "equator"). The development of this pattern depends on two systems of positional information that inform the cluster of cells that will form an ommatidium of anterior/posterior (a/p) and dorsal/ventral (d/v) direction. The former (a/p) is encoded by a progressive wave of development (the morphogenetic furrow). The latter (d/v) involves molecules known to act in tissue polarity in other organs and organisms. Our understanding of the function of these molecules rests not only on their mutant phenotypes, biochemistry, and expression patterns, but also on the spatial effects when mutant patches of cells are made (genetic mosaics).

Animals↗
PubMed1999

Role of the EGF receptor pathway in growth and patterning of the Drosophila wing through the regulation of vestigial.

Growth and patterning of the Drosophila wing disc depends on the coordinated expression of the key regulatory gene vestigial both in the Dorsal-Ventral (D/V) boundary cells and in the wing pouch. We propose that a short-range signal originating from the core of the D/V boundary cells is responsible for activating EGFR in a zone of organizing cells on the edges of the D/V boundary. Using loss-of-function mutations and ectopic expression studies, we show that EGFR signaling is essential for vestigial transcription in these cells and for making them competent to undergo subsequent vestigial-mediated proliferation within the wing pouch.

Animals↗
PubMed1998

Ecdysone pathway is required for furrow progression in the developing Drosophila eye.

In Drosophila, secretion of the steroid hormone ecdysone from the prothoracic ring gland coordinates and triggers events such as molting and metamorphosis. In the developing Drosophila compound eye, pattern formation and cell-type specification initiate at a moving boundary known as the morphogenetic furrow. We have investigated the role of ecdysone in eye development and report here that the ecdysone signaling pathway is required for progression of the morphogenetic furrow in the eye imaginal disc of Drosophila. Genetic disruption both of the ecdysone signal in vivo with the ecdysoneless1 (ecd1) mutant and of ecdysone response with a Broad-Complex mutant result in disruption of morphogenetic furrow progression. In addition, we show that ecdysone-dependent gene expression, both of a reporter of transcriptional activity of the Ecdysone Receptor and of the Z1 isoform of the Broad Complex, are localized in and close to the furrow. These results suggest that, in the morphogenetic furrow, temporal hormonal signals are integrated into genetic pathways specifying spatial pattern.

Animals↗
PubMed1998

Dissecting the roles of the Drosophila EGF receptor in eye development and MAP kinase activation.

A new conditional Egfr allele was used to dissect the roles of the receptor in eye development and to test two published models. EGFR function is necessary for morphogenetic furrow initiation, is not required for establishment of the founder R8 cell in each ommatidium, but is necessary to maintain its differentiated state. EGFR is required subsequently for recruitment of all other neuronal cells. The initial EGFR-dependent MAP kinase activation occurs in the furrow, but the active kinase (dp-ERK) is observed only in the cytoplasm for over 2 hours. Similarly, SEVENLESS-dependent activation results in cytoplasmic appearance of dp-ERK for 6 hours. These results suggest an additional regulated step in this pathway and we discuss models for this.

Alleles↗
PubMed1997

A polarity field is established early in the development of the Drosophila compound eye.

The photoreceptors within the ommatidia of the Drosophila compound eye form a trapezoid. This occurs in two chiral forms in the dorsal and ventral half of the eye. We have used two manipulations to induce ectopic ommatidia, in combination with molecular markers for specific positions in the retinal field. We find that ectopic morphogenetic furrows induced on the eye field margin (or midline) and those induced in the body of the field have different consequences for the establishment of retinal polarity. Furthermore, the dorsal/ventral vector field is established early in development, prior to and independent of the initiation of the morphogenetic furrow. An 'early equator' model is presented to account for these and previously published data.

Animals↗
PubMed1997

Complex formation between p53 and replication protein A inhibits the sequence-specific DNA binding of p53 and is regulated by single-stranded DNA.

Human replication protein A (RP-A) (also known as human single-stranded DNA binding protein, or HSSB) is a multisubunit complex involved in both DNA replication and repair. Potentially important to both these functions, it is also capable of complex formation with the tumor suppressor protein p53. Here we show that although p53 is unable to prevent RP-A from associating with a range of single-stranded DNAs in solution, RP-A is able to strongly inhibit p53 from functioning as a sequence-specific DNA binding protein when the two proteins are complexed. This inhibition, in turn, can be regulated by the presence of various lengths of single-stranded DNAs, as RP-A, when bound to these single-stranded DNAs, is unable to interact with p53. Interestingly, the lengths of single-stranded DNA capable of relieving complex formation between the two proteins represent forms that might be introduced through repair and replicative events. Increasing p53 concentrations can also overcome the inhibition by steady-state levels of RP-A, potentially mimicking cellular points of balance. Finally, it has been shown previously that p53 can itself be stimulated for site-specific DNA binding when complexed through the C terminus with short single strands of DNA, and here we show that p53 stays bound to these short strands even after binding a physiologically relevant site. These results identify a potential dual role for single-stranded DNA in the regulation of DNA binding by p53 and give insights into the p53 response to DNA damage.

Amino Acid Sequence↗
PubMed1997

The Drosophila TGF alpha homolog Spitz acts in photoreceptor recruitment in the developing retina.

In vertebrates and Drosophila, the Epidermal Growth Factor Receptor (EGFR) signal transduction pathway is important in the regulation of cellular development. EGFR is bound by several activating ligands including Transforming Growth Factor-alpha in vertebrates, and its homolog Spitz in Drosophila. It has been shown that Spitz and EGFR act in the development of the Drosophila central nervous system and compound eye. Here we show that spitz function is required in developing ommatidia for the first cell recruitment step, and that Spitz pro-protein is expressed in the retinal neurons as they begin to differentiate. We propose a 'two-key' model for additive signal transduction from EGFR and other receptor tyrosine kinases, via the Ras pathway, in the developing eye.

Animals↗