Spinophilin: from partners to functions

Cyclin E together with its kinase partner Cdk2 is a critical regulator of entry into S phase. To identify novel genes that regulate the G1- to S-phase transition within a whole animal we made use of a hypomorphic cyclin E mutation, DmcycEJP, which results in a rough eye phenotype. We screened the X and third chromosome deficiencies, tested candidate genes, and carried out a genetic screen of 55,000 EMS or X-ray-mutagenized flies for second or third chromosome mutations that dominantly modified the DmcycEJP rough eye phenotype. We have focused on the DmcycEJP suppressors, S(DmcycEJP), to identify novel negative regulators of S-phase entry. There are 18 suppressor gene groups with more than one allele and several genes that are represented by only a single allele. All S(DmcycEJP) tested suppress the DmcycEJP rough eye phenotype by increasing the number of S phases in the postmorphogenetic furrow S-phase band. By testing candidates we have identified several modifier genes from the mutagenic screen as well as from the deficiency screen. DmcycEJP suppressor genes fall into the classes of: (1) chromatin remodeling or transcription factors; (2) signaling pathways; and (3) cytoskeletal, (4) cell adhesion, and (5) cytoarchitectural tumor suppressors. The cytoarchitectural tumor suppressors include scribble, lethal-2-giant-larvae (lgl), and discs-large (dlg), loss of function of which leads to neoplastic tumors and disruption of apical-basal cell polarity. We further explored the genetic interactions of scribble with S(DmcycEJP) genes and show that hypomorphic scribble mutants exhibit genetic interactions with lgl, scab (αPS3-integrin—cell adhesion), phyllopod (signaling), dEB1 (microtubule-binding protein—cytoskeletal), and moira (chromatin remodeling). These interactions of the cytoarchitectural suppressor gene, scribble, with cell adhesion, signaling, cytoskeletal, and chromatin remodeling genes, suggest that these genes may act in a common pathway to negatively regulate cyclin E or S-phase entry.

https://www.genetics.org/content/genetics/168/1/227.full.pdf

A Genetic Screen for Dominant Modifiers of a cyclin E Hypomorphic Mutation Identifies Novel Regulators of S-Phase Entry in Drosophila

Here I present a deterministic model of the coevolution of parasites with the acquired immunity of their hosts, a system in which coevolutionary oscillations can be maintained. These dynamics can confer an advantage to sexual reproduction within the parasite population, but the effect is not strong enough to outweigh the twofold cost of sex. The advantage arises primarily because sexual reproduction impedes the response to fluctuating epistasis and not because it facilitates the response to directional selection-in fact, sexual reproduction often slows the response to directional selection. Where the cost of sexual reproduction is small, a polymorphism can be maintained between the sexuals and the asexuals. A polymorphism is maintained in which the advantage gained due to recombination is balanced by the cost of sex. At much higher costs of sex, a polymorphism between the asexual and sexual populations can still be maintained if the asexuals do not have a full complement of genotypes available to them, because the asexuals only outcompete those sexuals with which they share the same selected alleles. However, over time we might expect the asexuals to amass the full array of genotypes, thus permanently eliminating sexuals from the population. The sexuals may avoid this fate if the parasite population is finite. Although the model presented here describes the coevolution of parasites with the acquired immune responses of their hosts, it can be compared with other host-parasite models that have more traditionally been used to investigate Red Queen theories of the evolution of sex.

https://www.jstor.org/stable/pdfplus/2640613.pdf

The coevolution of parasites with host-acquired immunity and the evolution of sex

It has been suggested that sexual reproduction in parasites may be advantageous because it helps evade genotype-specific host immune responses. Indirect support for this hypothesis has recently come from work on Strongyloides ratti, a parasitic nematode of rats that develops and reproduces sexually or asexually. In this species, host immune responses against S. ratti lead to a higher proportion of individuals reproducing sexually. However, an alternative explanation for these results is that sex is favoured by general environmental stress, including host responses against antigen sources other than S. ratti. Here we test this hypothesis, by determining how host immunity against two other parasitic nematode species (Nippostrongylus brasiliensis & Strongyloides venezuelensis) and commonly used mammalian antigens (sheep red blood cells) affects the likelihood of S. ratti larvae developing sexually. Our results show that increased levels of sex occur in response to immune responses generated against these other species, and not just host immunity elicited by S. ratti. This is consistent with the idea that sex is favoured under stressful conditions, and does not support the immune evasion hypothesis.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1420-9101.2001.00266.x

Immune stress and facultative sex in a parasitic nematode

Mitochondrial disease in flies

At the onset of metamorphosis in Drosophila melanogaster, the steroid hormone 20-OH ecdysone induces a small number of early and early-late puffs in the polytene chromosomes of the third-instar larval salivary gland whose activity is required for regulating the activity of a larger set of late puffs. Most of the corresponding early and early-late genes have been found to encode transcription factors that regulate a much larger set of late genes. In contrast, we describe here the identification of an ecdysone-regulated gene in the 62E early-late puff, denoted D-spinophilin, that encodes a protein similar to the mammalian protein spinophilin/neurabin II. The D-spinophilin protein is predicted to contain a highly conserved PP1-binding domain and adjacent PDZ domain, as well as a coiled-coil domain and SAM domain, and belongs to a family of related proteins from diverse organisms. Transcription of D-spinophilin is correlated with 62E puff activity during the early stages of metamorphosis and is ecdysone-dependent, making this the first member of this gene family shown to be regulated by a steroid hormone. Examination of the dynamic patterns of D-spinophilin expression during the early stages of metamorphosis are consistent with a role in central nervous system metamorphosis as well as a more general role in other tissues. As D-spinophilin appears to be the only member of this gene family in Drosophila, its study provides an excellent opportunity to elucidate the role of an important adaptor protein in a genetic model organism.

The 62E early-late puff of Drosophila contains D-spinophilin, an ecdysone-inducible PDZ-domain protein dynamically expressed during metamorphosis.

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The 62E early-late puff of Drosophila contains D-spinophilin, an ecdysone-inducible PDZ-domain protein dynamically expressed during metamorphosis.