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1.
PLoS Genet ; 16(12): e1008948, 2020 12.
Article in English | MEDLINE | ID: mdl-33320862

ABSTRACT

During metazoan development, the cell cycle is remodelled to coordinate proliferation with differentiation. Developmental cues cause dramatic changes in the number and timing of replication initiation events, but the mechanisms and physiological importance of such changes are poorly understood. Cyclin-dependent kinases (CDKs) are important for regulating S-phase length in many metazoa, and here we show in the nematode Caenorhabditis elegans that an essential function of CDKs during early embryogenesis is to regulate the interactions between three replication initiation factors SLD-3, SLD-2 and MUS-101 (Dpb11/TopBP1). Mutations that bypass the requirement for CDKs to generate interactions between these factors is partly sufficient for viability in the absence of Cyclin E, demonstrating that this is a critical embryonic function of this Cyclin. Both SLD-2 and SLD-3 are asymmetrically localised in the early embryo and the levels of these proteins inversely correlate with S-phase length. We also show that SLD-2 asymmetry is determined by direct interaction with the polarity protein PKC-3. This study explains an essential function of CDKs for replication initiation in a metazoan and provides the first direct molecular mechanism through which polarization of the embryo is coordinated with DNA replication initiation factors.


Subject(s)
Body Patterning , Caenorhabditis elegans Proteins/genetics , Cyclin-Dependent Kinases/metabolism , DNA Replication , Animals , Caenorhabditis elegans , Caenorhabditis elegans Proteins/metabolism , Cyclin-Dependent Kinases/genetics , Mutation , Protein Kinase C/genetics , Protein Kinase C/metabolism
2.
Cell Rep ; 23(10): 2835-2843.e4, 2018 06 05.
Article in English | MEDLINE | ID: mdl-29874571

ABSTRACT

Switching between alternative complex phenotypes is often regulated by "supergenes," polymorphic clusters of linked genes such as in butterfly mimicry. In contrast, phenotypic plasticity results in alternative complex phenotypes controlled by environmental influences rather than polymorphisms. Here, we show that the developmental switch gene regulating predatory versus non-predatory mouth-form plasticity in the nematode Pristionchus pacificus is part of a multi-gene locus containing two sulfatases and two α-N-acetylglucosaminidases (nag). We provide functional characterization of all four genes, using CRISPR-Cas9-based reverse genetics, and show that nag genes and the previously identified eud-1/sulfatase have opposing influences. Members of the multi-gene locus show non-overlapping neuronal expression and epistatic relationships. The locus architecture is conserved in the entire genus Pristionchus. Interestingly, divergence between paralogs is counteracted by gene conversion, as inferred from phylogenies and genotypes of CRISPR-Cas9-induced mutants. Thus, we found that physical linkage accompanies regulatory linkage between switch genes controlling plasticity in P. pacificus.


Subject(s)
Adaptation, Physiological/genetics , Conserved Sequence , Genes, Developmental , Genetic Loci , Animals , Base Sequence , Body Patterning , Evolution, Molecular , Gene Conversion , Genes, Helminth , Interneurons/metabolism , Nematoda/genetics , Nematoda/physiology , Phenotype , Sensory Receptor Cells/metabolism , Synteny/genetics
3.
Curr Biol ; 26(16): 2174-9, 2016 08 22.
Article in English | MEDLINE | ID: mdl-27451902

ABSTRACT

Developmental plasticity, the ability of one genotype to produce distinct phenotypes in different environments, has been suggested to facilitate phenotypic diversification, and several examples in plants and animals support its macroevolutionary potential [1-8]. However, little is known about associated molecular mechanisms, because environmental effects on development are difficult to study by laboratory approaches. One promising system is the mouth dimorphism of the nematode Pristionchus pacificus [9-12]. Following an irreversible decision in larval development, these nematodes form moveable teeth that occur in either of two discrete morphs. The "eurystomatous" (Eu) form has a wide mouth and two teeth, allowing predatory feeding on other nematodes. In contrast, the alternative ("stenostomatous"; St) form has diminutive mouthparts that largely constrain its diet to microbes. The sulfatase EUD-1 was previously discovered to execute a polyphenism switch based on dosage of functional alleles [13] and confirmed a prediction of evolutionary theory about how developmental switches control plasticity [1, 3]. However, the genetic context of this single gene, and hence the molecular complexity of switch mechanisms, was previously unknown. Here we use a suppressor screen to identify factors downstream of eud-1 in mouth-form regulation. We isolated three dominant, X-linked mutants in the nuclear hormone receptor gene nhr-40 that are haploinsufficient. Both eud-1 nhr-40 double and nhr-40 single mutants are all Eu, whereas transgenic overexpression of nhr-40 does not restore the wild-type phenotype but instead results in nearly all-St lines. Thus, NHR-40 is part of a developmental switch, suggesting that switch mechanisms controlling plasticity consist of multi-component hormonal signaling systems.


Subject(s)
Receptors, Cytoplasmic and Nuclear/genetics , Rhabditida/genetics , Sulfatases/genetics , Animals , Gene Expression Regulation, Developmental , Hermaphroditic Organisms/genetics , Hermaphroditic Organisms/growth & development , Larva/anatomy & histology , Larva/genetics , Larva/growth & development , Male , Mouth/anatomy & histology , Phenotype , Receptors, Cytoplasmic and Nuclear/metabolism , Rhabditida/anatomy & histology , Rhabditida/growth & development , Sulfatases/metabolism , Tooth/anatomy & histology
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