The mapping locus is encoded by a gain-of-function mutation in .

We mapped to the locus (encoded by the gene W01F3.3) on the far-right end of chromosome V. The canonical allele of , , is an in-frame deletion in a conserved exon of the protein that creates a gain-of-function roller phenotype.

Interpretation of BRCA2 Splicing Variants: A Case Series of Challenging Variant Interpretations and the Importance of Functional RNA Analysis.

A substantial proportion of pathogenic variants associated with an increased risk of hereditary cancer are sequence variants affecting RNA splicing. The classification of these variants can be complex when both non-functional and functional transcripts are produced from the variant allele. We present four BRCA2 splice site variants with complex variant interpretations (BRCA2 c.

Axotomy-induced HIF-serotonin signalling axis promotes axon regeneration in C. elegans.

The molecular mechanisms underlying the ability of axons to regenerate after injury remain poorly understood. Here we show that in Caenorhabditis elegans, axotomy induces ectopic expression of serotonin (5-HT) in axotomized non-serotonergic neurons via HIF-1, a hypoxia-inducible transcription factor, and that 5-HT subsequently promotes axon regeneration by autocrine signalling through the SER-7 5-HT receptor. Furthermore, we identify the rhgf-1 and rga-5 genes, encoding homologues of RhoGEF and RhoGAP, respectively, as regulators of axon regeneration.

Axon regeneration genes identified by RNAi screening in C. elegans.

Axons of the mammalian CNS lose the ability to regenerate soon after development due to both an inhibitory CNS environment and the loss of cell-intrinsic factors necessary for regeneration. The complex molecular events required for robust regeneration of mature neurons are not fully understood, particularly in vivo. To identify genes affecting axon regeneration in Caenorhabditis elegans, we performed both an RNAi-based screen for defective motor axon regeneration in unc-70/β-spectrin mutants and a candidate gene screen.

Molecular antagonism between X-chromosome and autosome signals determines nematode sex.

Sex is determined in Caenorhabditis elegans by the ratio of X chromosomes to the sets of autosomes, the X:A signal. A set of genes called X signal elements (XSEs) communicates X-chromosome dose by repressing the masculinizing sex determination switch gene xol-1 (XO lethal) in a dose-dependent manner. xol-1 is active in 1X:2A embryos (males) but repressed in 2X:2A embryos (hermaphrodites).

Endocannabinoid-Goα signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqα-PKC-JNK signalling.

The ability of neurons to regenerate their axons after injury is determined by a balance between cellular pathways that promote and those that inhibit regeneration. In Caenorhabditis elegans, axon regeneration is positively regulated by the c-Jun N-terminal kinase mitogen activated protein kinase pathway, which is activated by growth factor-receptor tyrosine kinase signalling. Here we show that fatty acid amide hydrolase-1, an enzyme involved in the degradation of the endocannabinoid anandamide (arachidonoyl ethanolamide), regulates the axon regeneration response of γ-aminobutyric acid neurons after laser axotomy.

DLK: the "preconditioning" signal for axon regeneration?

In this issue of Neuron, Shin et al. (2012) show that the dual leucine zipper kinase (DLK) is responsible for the retrograde injury signal in spinal sensory and motor neurons. DLK is required for the accelerated regeneration seen after axotomy and for the improved regeneration seen after a conditioning injury.

The growth factor SVH-1 regulates axon regeneration in C. elegans via the JNK MAPK cascade.

The ability of neurons to undergo regenerative growth after injury is governed by cell-intrinsic and cell-extrinsic regeneration pathways. These pathways represent potential targets for therapies to enhance regeneration. However, the signaling pathways that orchestrate axon regeneration are not well understood.

Constructing a low-budget laser axotomy system to study axon regeneration in C. elegans.

Laser axotomy followed by time-lapse microscopy is a sensitive assay for axon regeneration phenotypes in C. elegans(1). The main difficulty of this assay is the perceived cost ($25-100K) and technical expertise required for implementing a laser ablation system(2,3).

Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways.

Signaling pathways essential for axon regeneration, but not for neuron development or function, are particularly well suited targets for therapeutic intervention. We find that the parallel PMK-3(p38) and KGB-1(JNK) MAPK pathways must be coordinately activated to promote axon regeneration. Axon regeneration fails if the activity of either pathway is absent.

Targeted gene deletions in C. elegans using transposon excision.

We developed a method, MosDEL, to generate targeted knockouts of genes in Caenorhabditis elegans by injection. We generated a double-strand break by mobilizing a Mos1 transposon adjacent to the region to be deleted; the double-stranded break is repaired using injected DNA as a template. Repair can delete up to 25 kb of DNA and simultaneously insert a positive selection marker.

Axon regeneration requires a conserved MAP kinase pathway.

Regeneration of injured neurons can restore function, but most neurons regenerate poorly or not at all. The failure to regenerate in some cases is due to a lack of activation of cell-intrinsic regeneration pathways. These pathways might be targeted for the development of therapies that can restore neuron function after injury or disease.

Meiotic crossover number and distribution are regulated by a dosage compensation protein that resembles a condensin subunit.

Biological processes that function chromosome-wide are not well understood. Here, we show that the Caenorhabditis elegans protein DPY-28 controls two such processes, X-chromosome dosage compensation in somatic cells and meiotic crossover number and distribution in germ cells. DPY-28 resembles a subunit of condensin, a conserved complex required for chromosome compaction and segregation.

Protons act as a transmitter for muscle contraction in C. elegans.

Muscle contraction is normally mediated by the release of neurotransmitters from motor neurons. Here we demonstrate that protons can act as a direct transmitter from intestinal cells to stimulate muscle contraction. During the C.

Sperm chromatin proteomics identifies evolutionarily conserved fertility factors.

Male infertility is a long-standing enigma of significant medical concern. The integrity of sperm chromatin is a clinical indicator of male fertility and in vitro fertilization potential: chromosome aneuploidy and DNA decondensation or damage are correlated with reproductive failure. Identifying conserved proteins important for sperm chromatin structure and packaging can reveal universal causes of infertility.