TheC. elegansVAPB homolog VPR-1 is a permissive signal for gonad development

Abstract

VAMP/synaptobrevin-associated proteins (VAPs) contain an N-terminal major sperm protein domain (MSPd) that is associated with amyotrophic lateral sclerosis. VAPs have an intracellular housekeeping function, as well as an extracellular signaling function mediated by the secreted MSPd. Here we show that the C. elegans VAP homolog VPR-1 is essential for gonad development. vpr-1 null mutants are maternal effect sterile due to arrested gonadogenesis following embryo hatching. Somatic gonadal precursor cells and germ cells fail to proliferate fully and complete their respective differentiation programs. Maternal or zygotic vpr-1 expression is sufficient to induce gonadogenesis and fertility. Genetic mosaic and cell type-specific expression studies indicate that vpr-1 activity is important in the nervous system, germ line and intestine. VPR-1 acts in parallel to Notch signaling, a key regulator of germline stem cell proliferation and differentiation. Neuronal vpr-1 expression is sufficient for gonadogenesis induction during a limited time period shortly after hatching. These results support the model that the secreted VPR-1 MSPd acts at least in part on gonadal sheath cell precursors in L1 to early L2 stage hermaphrodites to permit gonadogenesis.

The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1

“…Both transgenes completely rescued the muscle mitochondria ( Fig. 2 B) and gonad development defects ( Cottee et al, 2017 ). We used two strategies to evaluate zygotic germline vpr-1 expression (see Materials and Methods).…”

“…Previous experiments showed that driving vpr-1 cDNA expression pan-neuronally using the unc-119 promoter rescued ∼30-40% of the muscle mitochondrial defects in vpr-1(tm1411) mutants ( Han et al, 2012 ). We found that vpr-1 genomic sequence, including the 3′ UTR, is more efficient than the cDNA with the unc-54 3′ UTR in rescuing the vpr-1 mutant gonadogenesis defect ( Cottee et al, 2017 ). Transgenes containing vpr-1 genomic DNA driven by pan-neuronal ( unc-119p ), GABA motor neuron ( unc-25p ), cholinergic motor neuron ( unc-17p ), head interneuron ( glr-5p ) or sensory neuron ( osm-6p ) specific promoters rescue the vpr-1 mutant muscle mitochondrial defects in about half the muscles, with variation apparent among animals ( Fig.…”

“…These data suggest that MSPd signaling via CLR-1 is sufficient in late larval and adult stages, when a major source of MSPd signals, the germ line, is expanding and differentiating. Temporally inducing vpr-1 expression in head neurons using the binary Q system ( Wei et al, 2012 ) also promoted muscle mitochondrial alignment ( Cottee et al, 2017 ).

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The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1

“…We found that vpr-1 genomic sequence, including the 3′ UTR, is more efficient than the cDNA with the unc-54 3′ UTR in rescuing the vpr-1 mutant gonadogenesis defect (Cottee et al, 2017). Transgenes containing vpr-1 genomic DNA driven by pan-neuronal (unc-119p), GABA motor neuron (unc-25p), cholinergic motor neuron (unc-17p), head interneuron (glr-5p) or sensory neuron (osm6p) specific promoters rescue the vpr-1 mutant muscle mitochondrial defects in about half the muscles, with variation apparent among animals ( Fig.…”

“…These data suggest that MSPd signaling via CLR-1 is sufficient in late larval and adult stages, when a major source of MSPd signals, the germ line, is expanding and differentiating. Temporally inducing vpr-1 expression in head neurons using the binary Q system (Wei et al, 2012) also promoted muscle mitochondrial alignment (Cottee et al, 2017).…”