UNC-108/RAB-2 and its effector RIC-19 are involved in dense core vesicle maturation in<i>Caenorhabditis elegans</i>

Sumakovic, Marija; Hegermann, Jan; Luo, Lin; Husson, Steven; Schwarze, Katrin; Olendrowitz, Christian; Schoofs, Liliane; Richmond, Janet E.; Eimer, Stefan

doi:10.1083/jcb.200902096

Cited by 94 publications

(190 citation statements)

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“…Thus, the EM data corroborate the quantitative fluorescence data and demonstrate that the cargos that are missing in axons correspond to similar reductions in actual DCVs, with only mild effects on SV numbers. This contrasts with unc-108 mutants, which are missing about two-thirds of their soluble and transmembrane DCV cargos, but have normal levels of actual DCVs and SVs in their axons Sumakovic et al 2009). …”

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confidence: 74%

“…The model organism Caenorhabditis elegans has several strengths for investigating neuronal DCV trafficking, including the ability to track and quantitatively image DCV cargos in live animals using fluorescently tagged cargos expressed from integrated transgenes, and the ability to perform large forward genetic screens to uncover the molecular requirements for DCV trafficking. Past studies used these strengths to show that null mutations in UNC-108 (Rab2) cause altered interactions between immature DCVs and early endosomes, resulting in the loss of soluble and transmembrane cargos without affecting the aggregated neuropeptide core Sumakovic et al 2009). …”

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confidence: 99%

“…Past studies used these strengths to show that null mutations in UNC-108 (Rab2) cause altered interactions between immature DCVs and early endosomes, resulting in the loss of soluble and transmembrane cargos without affecting the aggregated neuropeptide core Sumakovic et al 2009). …”

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A Novel CaM Kinase II Pathway Controls the Location of Neuropeptide Release fromCaenorhabditis elegansMotor Neurons

Hoover

Edwards

et al. 2014

Genetics

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Neurons release neuropeptides via the regulated exocytosis of dense core vesicles (DCVs) to evoke or modulate behaviors. We found that Caenorhabditis elegans motor neurons send most of their DCVs to axons, leaving very few in the cell somas. How neurons maintain this skewed distribution and the extent to which it can be altered to control DCV numbers in axons or to drive release from somas for different behavioral impacts is unknown. Using a forward genetic screen, we identified loss-of-function mutations in UNC-43 (CaM kinase II) that reduce axonal DCV levels by 90% and cell soma/dendrite DCV levels by 80%, leaving small synaptic vesicles largely unaffected. Blocking regulated secretion in unc-43 mutants restored near wild-type axonal levels of DCVs. Time-lapse video microscopy showed no role for CaM kinase II in the transport of DCVs from cell somas to axons. In vivo secretion assays revealed that much of the missing neuropeptide in unc-43 mutants is secreted via a regulated secretory pathway requiring UNC-31 (CAPS) and . DCV cargo levels in unc-43 mutants are similarly low in cell somas and the axon initial segment, indicating that the secretion occurs prior to axonal transport. Genetic pathway analysis suggests that abnormal neuropeptide function contributes to the sluggish basal locomotion rate of unc-43 mutants. These results reveal a novel pathway controlling the location of DCV exocytosis and describe a major new function for CaM kinase II. BOTH neurons and neuroendocrine cells rely on the controlled release of neuropeptides via dense core vesicle (DCV) exocytosis to evoke or modulate behaviors (Scheller and Axel 1984;Kupfermann 1991;T. Liu et al. 2007;Li and Kim 2008). The DCVs in neuroendocrine and PC12 cells are much more abundant and accessible to biochemical and physiological experiments than those in neurons. For example, in chromaffin and pancreatic b-cells (both neuroendocrine cells), DCVs can number in the tens of thousands per cell and can occupy 31 and 12% of the cell volume, respectively (Dean 1973;Plattner et al. 1997). Exploiting these advantages, studies in PC12 and neuroendocrine cells have revealed that DCVs arise from a regulated secretory pathway. The pathway begins in the trans Golgi, where various sorting mechanisms cause regulated secretory proteins, such as neuropeptides and their processing enzymes, to coalesce into vesicles that bud from the trans Golgi to form immature DCVs. Additional sorting of non-DCV cargos away from DCV cargos occurs as DCVs mature through this pathway (Arvan and Castle 1998;Tooze et al. 2001;Borgonovo et al. 2006).DCVs must selectively retain and protect several distinct cargos that have different physical states as they mature. These include the neuropeptide core, which is thought to be in an aggregated state, the neuropeptide-processing enzymes PC-2 convertase and carboxypeptidase E, possibly soluble cargos, and transmembrane cargos.While neurons and neuroendocrine cells share this core pathway for DCV production, neurons have evolved additional...

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A Novel CaM Kinase II Pathway Controls the Location of Neuropeptide Release fromCaenorhabditis elegansMotor Neurons

Hoover

Edwards

et al. 2014

Genetics

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“…It is required for proper vesicle transport from the endoplasmic reticulum to the Golgi. Rab2 is also involved in the biogenesis of dense core vesicles, a form of neuropeptide release (Edwards et al 2009;Sumakovic et al 2009). Rim is an adaptor protein localized to the presynaptic zone of a neuron.…”

Section: Association Of Female Snps With Sperm Competitionmentioning

confidence: 99%

Large Neurological Component to Genetic Differences Underlying Biased Sperm Use in Drosophila

2013

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Sperm competition arises as a result of complex interactions among male and female factors. While the roles of some male factors are known, little is known of the molecules or mechanisms that underlie the female contribution to sperm competition. The genetic tools available for Drosophila allow us to identify, in an unbiased manner, candidate female genes that are critical for mediating sperm competition outcomes. We first screened for differences in female sperm storage and use patterns by characterizing the natural variation in sperm competition in a set of 39 lines from the sequenced Drosophila Genetic Reference Panel (DGRP) of wild-derived inbred lines. We found extensive female variation in sperm competition outcomes. To generate a list of candidate female genes for functional studies, we performed a genome-wide association mapping, utilizing the common single-nucleotide polymorphisms (SNPs) segregating in the DGRP lines. Surprisingly, SNPs within ion channel genes and other genes with roles in the nervous system were among the top associated SNPs. Knockdown studies of three candidate genes (para, Rab2, and Rim) in sensory neurons innervating the female reproductive tract indicate that some of these candidate female genes may affect sperm competition by modulating the neural input of these sensory neurons to the female reproductive tract. More extensive functional studies are needed to elucidate the exact role of all these candidate female genes in sperm competition. Nevertheless, the female nervous system appears to have a previously unappreciated role in sperm competition. Our results indicate that the study of female control of sperm competition should not be limited to female reproductive tract-specific genes, but should focus also on diverse biological pathways. I N many organisms, sperm competition is an important source of reproductive variation and is critical to the reproductive success of both males and females. Sperm competition occurs when a female mates with and stores sperm from multiple males. Multiple mating creates a situation in which the males' sperm "compete" for successful fertilizations. While the ultimate outcome of a sperm competition depends on a complex interaction between male and female factors, the sexes often have different interests. Males are essentially in competition with other males, and while natural selection drives males to become better competitors with each other, it may result in males damaging the female through toxicity of seminal proteins (Wigby and Chapman 2004;Mueller et al. 2007). On the other hand, females benefit from simply being able to produce the most and highest-fitness offspring, and this may entail a specific response to male-produced molecules that influence sperm competition. The sexual conflict that arises from these different evolutionary goals of males and females implies that the genetic response to selection on sperm competition may be totally distinct in males and females. It remains largely unknown what genes drive this sexual antagon...

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“…However, apart from physical aggregation, little is understood about how DCV cargos are retained within DCVs while factors not destined for DCVs are directed to the endosomal/lysosomal route during DCV maturation. An important insight comes from a study in Caenorhabditis elegans showing that loss of Rab2a function leads to specific lysosomal degradation of a neuropeptide that is normally located in DCVs (Sumakovic et al, 2009). However, the existence of such a mechanism in mammalian cells has not been demonstrated.…”

Section: The Cellular Processes Modulated By Commensal Bacteria In Pamentioning

confidence: 99%

Paneth cells: the hub for sensing and regulating intestinal flora

Zhang

Liu

2016

Sci. China Life Sci.

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The complex interplay between symbiotic bacteria and host immunity plays a key role in shaping intestinal homeostasis and maintaining host health. Paneth cells, as one of the major producers of antimicrobial peptides in the intestine under steady-state conditions, play a vital role in regulating intestinal flora. Many studies on inflammatory bowel disease (IBD)-associated genes have put Paneth cells at the center of IBD pathogenesis. In this perspective, we focus on mechanistic studies of different cellular processes in Paneth cells that are regulated by various IBD-associated susceptibility genes, and we discuss the hypothesis that Paneth cells function as the central hub for sensing and regulating intestinal flora in the maintenance of intestinal homeostasis. inflammatory bowel disease, Paneth cell, commensal bacteria, intestinal homeostasisCitation:

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UNC-108/RAB-2 and its effector RIC-19 are involved in dense core vesicle maturation inCaenorhabditis elegans

Abstract: Uncoordinated movement in Rab2 mutants is caused by impaired retention of cargo on dense core vesicles, not by defective synaptic vesicle release. (Also see the companion article by Edwards et al. in this issue.)

Cited by 94 publications

References 59 publications

A Novel CaM Kinase II Pathway Controls the Location of Neuropeptide Release fromCaenorhabditis elegansMotor Neurons

A Novel CaM Kinase II Pathway Controls the Location of Neuropeptide Release fromCaenorhabditis elegansMotor Neurons

Large Neurological Component to Genetic Differences Underlying Biased Sperm Use in Drosophila

Paneth cells: the hub for sensing and regulating intestinal flora

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