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M W Young

Publications and source records attributed to M W Young.

At least 55 records · Page 3Linked to original sources
PubMed1994

Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless.

Eclosion, or emergence of adult flies from the pupa, and locomotor activity of adults occur rhythmically in Drosophila melanogaster, with a circadian period of about 24 hours. Here, a clock mutation, timeless (tim), is described that produces arrhythmia for both behaviors. The effects of tim on behavioral rhythms are likely to involve products of the X chromosome-linked clock gene period (per), because tim alters circadian oscillations of per RNA. Genetic mapping places tim on the left arm of the second chromosome between dumpy (dp) and decapentaplegic (dpp).

Animals↗
PubMed1994

Block in nuclear localization of period protein by a second clock mutation, timeless.

In wild-type Drosophila, the period protein (PER) is found in nuclei of the eyes and brain, and PER immunoreactivity oscillates with a circadian rhythm. The studies described here indicate that the nuclear localization of PER is blocked by timeless (tim), a second chromosome mutation that, like per null mutations, abolishes circadian rhythms. PER fusion proteins without a conserved domain (PAS) and some flanking sequences are nuclear in tim mutants. This suggests that a segment of PER inhibits nuclear localization in tim mutants. The tim gene may have a role in establishing rhythms of PER abundance and nuclear localization in wild-type flies.

Animals↗
PubMed1994

Igloo, a GAP-43-related gene expressed in the developing nervous system of Drosophila.

GAP-43 (growth-associated protein, 43 x 10(3) M(r)) is an essential, membrane-associated, neuronal phosphoprotein in vertebrates. The protein is abundantly produced in the growth cones of developing and regenerating neurons, and it is phosphorylated upon induction of long-term potentiation (LTP). Prior work has identified GAP-43-like proteins only in chordates. In this paper, a nervous system-specific gene from Drosophila melanogaster is described that encodes two proteins sharing biochemical activities and sequence homology with GAP-43. The region of homology encompasses the calmodulin-binding domain and protein kinase C (PKC) phosphorylation site of GAP-43. The fly proteins are shown to bind Drosophila calmodulin (CaM), and are phosphorylated by purified PKC after a fashion predicted from prior work with vertebrate GAP-43. GAP-43 is modified by palmitoylation. An amino-terminal myristoylation site is described for the Drosophila protein, which may play a similar role in membrane association in the fly. While a small family of GAP-43-related genes has been recognized in vertebrates, only a single gene appears to be present in the fly. As the Drosophila gene encodes two proteins, each with multiple calmodulin-binding domains and repeated sites for PKC phosphorylation, it may afford functions provided by the family of vertebrate genes.

Amino Acid Sequence↗
PubMed1993

Further evidence for function of the Drosophila Notch protein as a transmembrane receptor.

N locus mutations associated with unusual mutant phenotypes were found to alter the structure of the encoded protein. Two mutations, NCo and N60g11, eliminate much of the cytoplasmic domain. NCo can act as a null allele or as a competitive inhibitor of N+ function, whereas N60g11 produces dominant gain of function in some cell types. This difference in function can be attributed to retention of cdc10/SWI6 repeats in the Notch60g11 protein. The results suggest a role for these repeats in intracellular signaling and are consistent with action of Notch as a receptor. nd3 and l(1)NB alter extracellular epidermal growth factor-like and lin-12/Notch elements, respectively. nd3 eliminates a conserved cysteine residue, so the mutation may result in complete loss of function for a single Notch epidermal growth factor element. N60g11 and l(1)NB produce related gain-of-function phenotypes. It is proposed that l(1)NB produces an extracellular modification of the protein that stimulates aberrant intracellular signaling by the Notch cytoplasmic domain.

Amino Acid Sequence↗
PubMed1993

Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei.

Loss of any one of several neurogenic genes of Drosophila results in overproduction of embryonic neuroblasts at the expense of epidermoblasts. In this paper a variety of altered Notch proteins are expressed in transgenic flies. Dominant lethal, antineurogenic phenotypes were produced by expression of three classes of mutant proteins: (1) a protein comprised of the cytoplasmic domain of Notch and devoid of sequences permitting membrane association; (2) a transmembrane protein lacking the extracellular, lin12/Notch repeats; and (3) transmembrane proteins carrying amino acid substitutions replacing one or both extracellular cysteines thought to be involved in Notch dimerization. These Notch proteins not only suppress the neural hypertrophy observed in Notch- embryos, but also generate a phenotype in which elements of the embryonic nervous system are underproduced. Action of the intracellular cdc10 repeats appears to be essential for wild-type Notch function or for the antineurogenic activity of these proteins. The activities of the dominant, gain-of-function proteins indicate that Notch functions as a signal transducing receptor during ectoderm development. Production of antineurogenic Notch proteins in embryos deficient for the other neurogenic genes allowed functional dependencies to be established. Delta, mastermind, bigbrain, and neuralized appear to function in elaboration of a signal upstream of Notch. Genes of the Enhancer of split complex act after Notch. The cytoplasmic domain of Notch contains nuclear localization sequences that function in cultured cells, and one of the Notch antineurogenic proteins, the cytoplasmic domain, accumulates in nuclei in vivo.

Animals↗
PubMed1992

Ontogeny of a biological clock in Drosophila melanogaster.

Drosophila melanogaster born and reared in constant darkness exhibit circadian locomotor activity rhythms as adults. However, the rhythms of the individual flies composing these populations are not synchronized with one another. This lack of synchrony is evident in populations of flies commencing development at the same time, indicating that a biological clock controlling circadian rhythmicity in Drosophila begins to function without a requirement for light and without a developmentally imparted phase. It is possible to synchronize the phases of rhythms produced by dark-reared flies with light treatments ending as early as the developmental transition from embryo to first-instar larva: Light treatments occurring at developmental times preceding hatching of the first-instar larva fail to synchronize adult locomotor activity rhythms, while treatments ending at completion of larval hatching entrain these rhythms. The synchronized rhythmic behavior of adult flies receiving such light treatments suggests that a clock controlling circadian rhythms may function continuously from the time of larval hatching to adulthood.

Age Factors↗
PubMed1992

New short period mutations of the Drosophila clock gene per.

Earlier work has indicated that the period length of Drosophila circadian behavioral rhythms is dependent on the abundance of the period (per) gene product. Increased expression of this gene has been associated with period shortening for both the circadian eclosion (pupal hatching) rhythm and circadian locomotor activity rhythms of adult Drosophila. In this study it is shown that a wide variety of missense mutations, affecting a region of the per protein consisting of approximately 20 aa, predominantly generate short period phenotypes. The prevalence of such mutations suggests that short period phenotypes may result from loss or depression of function in this domain of the per protein. Possibly mutations in the region eliminate a regulatory function provided by this segment, or substantially increase stability of the mutant protein.

Amino Acid Sequence↗
PubMed1992

Single amino acid substitutions in EGF-like elements of Notch and Delta modify Drosophila development and affect cell adhesion in vitro.

Notch locus EGF-like element mutations spl, altering eye development, and AxE2, affecting wing and sensilla development, are modified by mutations at Delta. It is shown that two allele-specific suppressors of spl involve single amino acid substitutions in the 4th (Dlsup5) and 9th (Dlsup4) EGF-like elements of the Delta protein. Cultured cells producing spl or AxE2 aggregate with cells producing wild-type Delta or Dlsup5 protein, and Dlsup5-producing cells adhere to cells producing wild-type Notch protein. However, spl,AxE2, and Dlsup5 are each defective in promoting these cell affinities, as none of the mutant proteins can compete with the corresponding wild-type proteins for formation of cell aggregates. Thus, widely separated EGF-like elements of Notch and Delta appear to participate in functional molecular interactions between the proteins. Dlsup5 does not improve adhesiveness of spl in vitro, so suppression in vivo may involve altered developmental signaling by spl-Dlsup5 complexes, rather than modified cell adhesion.

Amino Acid Sequence↗
PubMed1991

A role for the Drosophila neurogenic genes in mesoderm differentiation.

The neurogenic genes of Drosophila have long been known to regulate cell fate decisions in the developing ectoderm. In this paper we show that these genes also control mesoderm development. Embryonic cells that express the muscle-specific gene nautilus are overproduced in each of seven neurogenic mutants (Notch, Delta, Enhancer of split, big brain, mastermind, neuralized, and almondex), at the apparent expense of neighboring, nonexpressing mesodermal cells. The mesodermal defect does not appear to be a simple consequence of associated neural hypertrophy, suggesting that the neurogenic genes may function similarly and independently in establishing cell fates in both ectoderm and mesoderm. Altered patterns of beta 3-tubulin and myosin heavy chain gene expression in the mutants indicate a role for the neurogenic genes in development of most visceral and somatic muscles. We propose that the signal produced by the neurogenic genes is a general one, effective in both ectoderm and mesoderm.

Animals↗
PubMed1989

Structure and distribution of the Notch protein in developing Drosophila.

Antibodies to Notch show that it is a stable, high-molecular-weight transmembrane glycoprotein, with epidermal growth factor (EGF)-like elements exposed on the cell surface. The protein is phosphorylated variably on serines of the cytoplasmic domain. Individual Notch polypeptide chains appear to be associated with one another by disulfide bonds, suggesting that homotypic interaction of these proteins is required for function. Immunocytochemistry has revealed striking features of Notch expression that might clarify its function: Cells of the ventral neurogenic ectoderm become conspicuously labeled with the protein prior to embryonic neurogenesis, and Notch appears to be associated with cells destined for both neural and epidermal lineages. High levels of Notch become restricted to neuroblasts as they delaminate from the embryonic ectoderm and are apposed to mesoderm. Mesodermal cells express Notch also, suggesting a possible involvement in neurogenesis, or an unknown role in mesoderm differentiation. In larvae and pupae, a correlation of expression and neuroblast mitotic activity is seen for many cells. Notch produced by a dividing neuroblast may persist on derivative cells, including terminally differentiated neurons and nerve processes. In the larval eye imaginal disk, strong Notch expression appears in the morphogenetic furrow, uniformly on cell surfaces as they cluster to form ommatidia. Expression persists on ommatidia after release from the furrow. These patterns suggest a role for Notch in position-dependent development in both initiation and maintenance of cell-surface interactions. In the eye and embryonic ectoderm, uniform expression on cells interacting to produce different developmental lineages from a single primordium suggests that Notch alone may not be sufficient to elaborate cell fates.

Animals↗
PubMed1988

In situ localization of the per clock protein during development of Drosophila melanogaster.

The per locus influences biological rhythms in Drosophila melanogaster. In this study, per transcripts and proteins were localized in situ in pupae and adults. Earlier genetic studies have demonstrated that per expression is required in the brain for circadian locomotor activity rhythms and in the thorax for ultradian rhythmicity of the Drosophila courtship song. per RNA and proteins were detected in a restricted group of cells in the eyes and optic lobes of the adult brain and in many cell bodies in the adult and pupal thoracic ganglia. per products were also found in the pupal ring gland complex, a tissue involved in rhythmic aspects of Drosophila development. Abundant expression was seen in gonadal tissue. No biological clock phenotypes have been reported for this tissue in any of the per mutants, per protein mapped to different subcellular locations in different tissues. The protein accumulated in or around nuclei in some cells and appeared to be cytoplasmic in others.

Animals↗
PubMed1987

Mutations altering the structure of epidermal growth factor-like coding sequences at the Drosophila Notch locus.

The Drosophila neurogenic protein Notch is largely composed of tandemly repeated copies of an epidermal growth factor-like sequence. Notch protein contains 36 EGF-like elements, but no two are identical. In the present study, eight mutations are correlated with single amino acid substitutions in EGF-homologous elements of this protein. Genetic analyses of the mutations and comparisons of DNA from mutant and wild-type flies indicate that differentiation of function exists among the tandemly repeated EGF-like sequences and that the total number of repeats and minor variations from the consensus repeat sequence are important for wild-type Notch protein function. One group of EGF-like repeats may be involved in the formation of functional Notch dimers or multimeric proteins. EGF-like elements in a second region of the Notch protein appear to govern its interaction with the product of Enhancer of split, another neurogenic locus of D. melanogaster.

Alleles↗
PubMed1987

Restriction of P-element insertions at the Notch locus of Drosophila melanogaster.

P elements move about the Drosophila melanogaster genome in a nonrandom fashion, preferring some chromosomal targets for insertion over others (J. C. J. Eeken, F. H. Sobels, V. Hyland, and A. P. Schalet, Mutat. Res. 150:261-275, 1985; W. R. Engels, Annu. Rev. Genet. 17:315-344, 1983; M. D. Golubovsky, Y. N. Ivanov, and M. M. Green, Proc. Natl. Acad. Sci. USA 74:2973-2975, 1977; M. J. Simmons and J. K. Lim, Proc. Natl. Acad. Sci. USA 77:6042-6046, 1980). Some of this specificity may be due to recognition of a particular DNA sequence in the target DNA; derivatives of an 8-base-pair consensus sequence are occupied by these transposable elements at many different chromosomal locations (K. O'Hare and G. M. Rubin, Cell 34:25-36, 1983). An additional level of specificity of P-element insertions is described in this paper. Of 14 mutations induced in the complex locus Notch by hybrid dysgenesis, 13 involved P-element insertions at or near the transcription start site of the gene. This clustering was not seen in other transposable element-induced mutations of Notch. DNA sequences homologous to the previously described consensus target for P-element insertion are not preferentially located in this region of the locus. The choice of a chromosomal site for integration appears to be based on more subtle variations in chromosome structure that are probably associated with activation or expression of the target gene.

Animals↗
PubMed1986

Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors.

The Notch locus is essential for proper differentiation of the ectoderm in Drosophila melanogaster. Notch corresponds to a 37-kilobase transcription unit that codes for a major 10.4-kilobase polyadenylated RNA. The DNA sequence of this transcription unit is presented, except for portions of the two largest intervening sequences. DNA sequences also were obtained from three Notch cDNA clones, allowing the 5' and 3' ends of the gene to be mapped, and the structures and locations of nine RNA coding regions to be determined. The major Notch transcript encodes a protein of 2,703 amino acids. The protein is probably associated with cell surfaces and carries an extracellular domain composed of 36 cysteine-rich repeating units, each of about 38 amino acids. The gene appears to have evolved by repeated tandem duplications of the DNA coding for the 38-amino-acid-long protein segments, followed by insertion of intervening sequences. These repeating protein segments are quite homologous to portions of mammalian clotting factors IX and X and to the product of the Caenorhabditis elegans developmental gene lin-12. They are also similar to mammalian growth hormones, typified by epidermal growth factor.

Amino Acid Sequence↗