Quinn CC et al. (2008) Curr Biol "CED-10/Rac1 mediates axon guidance by regulating the asymmetric distribution of MIG-10/lamellipodin."

Quinn CC, Wadsworth WG, Pfeil DS

[Curr Biol, 2008]

Axon migrations are guided by extracellular cues that induce asymmetric outgrowth activity in the growth cone [1, 2]. Several intracellular signaling proteins have been implicated in the guidance response [3-10]. However, how these proteins interact to generate asymmetric outgrowth activity is unknown. Here, we present evidence that in C. elegans, the CED-10/Rac1 GTPase binds to and causes asymmetric localization of MIG-10/lamellipodin, a protein that regulates actin polymerization and has outgrowth-promoting activity in neurons [5, 11]. Genetic analysis indicates that mig-10 and ced-10 function together to orient axon outgrowth. The RAPH domain of MIG-10 binds to activated CED-10/Rac1, and ced-10 function is required for the asymmetric MIG-10 localization that occurs in response to the UNC-6/netrin guidance cue. We also show that asymmetric localization of MIG-10 in growth cones is associated with asymmetric concentrations of f-actin and microtubules. These results suggest that CED-10/Rac1 is asymmetrically activated in response to the UNC-6/netrin signal and thereby causes asymmetric recruitment of MIG-10/lamellipodin. We propose that the interaction between activated CED-10/Rac1 and MIG-10/lamellipodin triggers local cytoskeletal assembly and polarizes outgrowth activity in response to UNC-6/netrin.

Liu H et al. (2017) J Cell Biol "LET-413/Erbin acts as a RAB-5 effector to promote RAB-10 activation during endocytic recycling."

Chen J, Liu H, Hang W, He J, Zhang W, Wang S, Cheng Z, Gao J, Zhou J, Yang C, Shi A

[J Cell Biol, 2017]

RAB-10/Rab10 is a master regulator of endocytic recycling in epithelial cells. To better understand the regulation of RAB-10 activity, we sought to identify RAB-10(GDP)-interacting proteins. One novel RAB-10(GDP)-binding partner that we identified, LET-413, is the Caenorhabditis elegans homologue of Scrib/Erbin. Here, we focus on the mechanistic role of LET-413 in the regulation of RAB-10 within the C. elegans intestine. We show that LET-413 is a RAB-5 effector and colocalizes with RAB-10 on endosomes, and the overlap of LET-413 with RAB-10 is RAB-5 dependent. Notably, LET-413 enhances the interaction of DENN-4 with RAB-10(GDP) and promotes DENN-4 guanine nucleotide exchange factor activity toward RAB-10. Loss of LET-413 leads to cytosolic dispersion of the RAB-10 effectors TBC-2 and CNT-1. Finally, we demonstrate that the loss of RAB-10 or LET-413 results in abnormal overextensions of lateral membrane. Hence, our studies indicate that LET-413 is required for DENN-4-mediated RAB-10 activation, and the LET-413-assisted RAB-5 to RAB-10 cascade contributes to the integrity of C. elegans intestinal epithelia.

Serre, Joel M. et al. (2022) MicroPubl Biol

Serre, Joel M., Hardin, Jeff

[MicroPubl Biol, 2022]

Dorsal intercalation of the embryonic epidermis in the Caenorhabditis elegans embryo is a promising system for genetic analysis of convergent extension, a conserved process in animal embryos. We sought to identify functionally important actin regulators in dorsal epidermal cells. A promising candidate is MIG-10, the single MIG-10/RIAM/Lamellipodin (MRL) family member in C. elegans. We endogenously tagged all mig-10 isoforms with mNeonGreen and analyzed mig-10 mutants using 4-dimensional microscopy. MIG-10::mNG is expressed prominently in muscle progenitors but is not detectable in the dorsal epidermis. mig-10(ct41) homozygotes complete dorsal intercalation in a manner indistinguishable from wildtype, indicating MIG-10 is not essential during dorsal intercalation.

Killian DJ et al. (2008) Dev Biol "SKR-1, a homolog of Skp1 and a member of the SCF(SEL-10) complex, regulates sex-determination and LIN-12/Notch signaling in C. elegans."

Johnson P, Killian DJ, Xue D, Otori M, Harvey E, Mitani S

[Dev Biol, 2008]

Sex-determination in Caenorhabditis elegans requires regulation of gene transcription and protein activity and stability. sel-10 encodes a WD40-repeat-containing F-box protein that likely mediates the ubiquitin-mediated degradation of important sex-determination factors. Loss of sel-10 results in a mild masculinization of hermaphrodites, whereas dominant alleles of sel-10, such as sel-10(n1074), cause a more severe masculinization, including a reversal of the life versus death decision in sex-specific neurons. To investigate about how sel-10 regulates sex-determination, we conducted a sel-10(n1074) suppressor screen and isolated a weak loss-of-function allele of skr-1, one of 21 Skp1-related genes in C. elegans. Skp1, Cullin, and F-box proteins, such as SEL-10, are components of the SCF E3 ubiquitin-ligase complex. We present genetic evidence that the sel-10(n1074) masculinization phenotype is dependent upon skr-1 and cul-1 activity. Furthermore, we show that the SKR-1(M140I) weak loss-of-function mutation interferes with SKR-1/SEL-10 binding. Unexpectedly, we found that the G567E substitution in SEL-10 caused by the n1074 allele impairs the binding of SEL-10 to SKR-1 and the dimerization of SEL-10, which may be important for SEL-10 function. Our results suggest that SKR-1, CUL-1 and SEL-10 constitute an SCF E3 ligase complex that plays an important role in modulating sex-determination and LIN-12/Notch signaling in C. elegans.

Custodia N et al. (2001) Ann N Y Acad Sci "Caenorhabditis elegans as an environmental monitor using DNA microarray analysis."

Callard IP, Novilla A, Wieland M, Li C, Custodia N, Won SJ, Novillo A

[Ann N Y Acad Sci, 2001]

In order to assist in the identification of possible endocrine disrupting chemicals (EDC) in groundwater, we are developing Caenorhabditis elegans as a high throughput bioassay system in which responses to EDC may be detected by gene expression using DNA microarray analysis. As a first step we examined gene expression patterns and vitellogenin responses of this organism to vertebrate steroid, in liquid culture. Western blotting showed the expected number and size of vitellogenin translation products after estrogen exposure. At 10(-9) M, vitellogenin decreased, but at 10(-7) and 10(-5), vitellogenin was increased. Testosterone (10(-5) M) increased the synthesis of vitellogenin, but progesterone-treated cultures (10(-5) M) had less vitellogenin. Using DNA microarray analysis, we examined the pattern of gene expression after progesterone (10(-5), 10(-7), and 10(-9) M), estrogen (10(-5) M) and testosterone (10(-9) M) exposure, with special attention to the traditional biomarker genes used in environmental studies [vitellogenin, cytochrome P450 (CYP), glutathione s-transferase (GST), metallothionein (MT), and heat shock proteins (HSP).] GST and P450 genes were affected by estrogen (10(-5) M) and progesterone (10(-5) and 10(-7) M) treatments. For vitellogenin genes, estrogen treatment (10(-5) M) caused overexpression of the vit-2 and vit-6 genes (2.68 and 3.25 times, respectively). After progesterone treatment (10(-7) M), the vit-5 and vit-6 were down-regulated and vit-1 up-regulated (3.59-fold). Concentrations of testosterone and progesterone at 10(-9) M did not influence the expression of the vit, CYP, or GST genes. Although the analysis is incomplete, and low doses and combinations of EDC need to be tested, these preliminary results indicate C. elegans may be a useful

Kim SK et al. (1990) Genes Dev "The Caenorhabditis elegans gene lin-10 is broadly expressed while required specifically for the determination of vulval cell fates."

Horvitz HR, Kim SK

[Genes Dev, 1990]

As a first step in a molecular dissection of the pathway controlling the determination of vulval cell fates in Caenorhabditis elegans, we have analyzed the gene lin-10. We show that loss-of-function mutations in this gene specifically prevent the induction of vulval cell lineages and result instead in the expression of hypodermal cell lineages. We isolated a transposon-insertion allele of lin-10 and used it to clone a genomic region that contains the lin-10 locus. The location of lin-10 within this region was determined by identifying a transcript affected by three independent lin-10 mutations and by delimiting the minimal segment of DNA sufficient to rescue the lin-10 mutant phenotype in germ line transformation experiments. The predicted lin-10 protein sequence is not similar to sequences in current data bases, suggesting that lin-10 defines a novel class of gene involved in the specification of cell fates. Although our genetic studies indicate that lin-10 is required specifically for the determination of vulval cell fates, lin-10 transcripts are present in cells other than vulval precursor cells. This result suggests that lin-10 may have a general but redundant role in development, functioning in diverse cell lineages to control cell fates. Alternatively, lin-10 may function specifically in vulval development, in which case lin-10 activity could be regulated at a post-transcriptional level or could have biological consequences only in conjunction with the products of other genes.

Dusenbery DB (1975) J Exp Zool "The avoidance of D-tryptophan by the nematode Caenorhabditis elegans."

Dusenbery DB

[J Exp Zool, 1975]

In chemotactic studies employing countercurrent separation the nematode Caenorhabditis elegans was found to avoid D-tryptophan with a threshold in the range 10(-4) to 10(-3) M. There was no response to L-tryptophan up to 10(-2) M although it appeared to partially inhibit the response to D-tryptophan.

Wang L et al. (2014) Biochem Biophys Res Commun "MIG-10 (Lamellipodin) stabilizes invading cell adhesion to basement membrane and is a negative transcriptional target of EGL-43 in C. elegans."

Wang Z, Shen W, Wang L, Matus D, Sherwood D, Lei S

[Biochem Biophys Res Commun, 2014]

Cell invasion through basement membrane (BM) occurs in many physiological and pathological contexts. MIG-10, the Caenorhabditis elegans Lamellipodin (Lpd), regulates diverse biological processes. Its function and regulation in cell invasive behavior remain unclear. Using anchor cell (AC) invasion in C. elegans as an in vivo invasion model, we have previously found that mig-10's activity is largely outside of UNC-6 (netrin) signaling, a chemical cue directing AC invasion. We have shown that MIG-10 is a target of the transcription factor FOS-1A and facilitates BM breaching. Combining genetics and imaging analyses, we report that MIG-10 synergizes with UNC-6 to promote AC attachment to the BM, revealing a functional role for MIG-10 in stabilizing AC-BM adhesion. MIG-10 is also required for F-actin accumulation in the absence of UNC-6. Further, we identify mig-10 as a transcriptional target negatively regulated by EGL-43A (C. elegans Evi-1 proto-oncogene), a transcription factor positively controlled by FOS-1A. The revelation of this negative regulation unmasks an incoherent feedforward circuit existing among fos-1, egl-43 and mig-10. Moreover, our study suggests the functional importance of the negative regulation on mig-10 expression by showing that excessive MIG-10 impairs AC invasion. Thus, we provide new insight into MIG-10's function and its complex transcriptional regulation during cell invasive behavior.

Whitfield CW et al. (1999) Mol Biol Cell "Basolateral localization of the Caenorhabditis elegans epidermal growth factor receptor in epithelial cells by the PDZ protein LIN-10."

Whitfield CW, Hekimi S, Kim SK, Benard C, Barnes TM

[Mol Biol Cell, 1999]

In Caenorhabditis elegans, the EGF receptor (encoded by let-23) is localized to the basolateral membrane domain of the epithelial vulval precursor cells, where it acts through a conserved Ras/MAP kinase signaling pathway to induce vulval differentiation. lin-10 acts in LET-23 receptor tyrosine kinase basolateral localization, because lin-10 mutations result in mislocalization of LET-23 to the apical membrane domain and cause a signaling defective (vulvaless) phenotype. We demonstrate that the previous molecular identification of lin-10 was incorrect, and we identify a new gene corresponding to the lin-10 genetic locus. lin-10 encodes a protein with regions of similarity to mammalian X11/mint proteins, containing a phosphotyrosine-binding and two PDZ domains. A nonsense lin-10 allele that truncates both PDZ domains only partially reduces lin-10 gene activity, suggesting that these protein interaction domains are not essential for LIN-10 function in vulval induction. Immunocytochemical experiments show that LIN-10 is expressed in vulval epithelial cells and in neurons. LIN-10 is present at low levels in the cytoplasm and at the plasma membrane and at high levels at or near the Golgi. LIN-10 may function in secretion of LET-23 to the basolateral membrane domain, or it may be involved in tethering LET-23 at the basolateral plasma membrane once it is secreted.

Honda Y et al. (2015) J Aging Res "10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling."

Hata T, Ichihara K, Honda S, Honda Y, Tanaka M, Ito M, Araki Y

[J Aging Res, 2015]

Royal jelly (RJ) produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA), the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan of Caenorhabditis elegans. The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA further extended the lifespan of the daf-2 mutants, which exhibit long lifespan through reducing insulin-like signaling (ILS), indicating that 10-HDA extended lifespan independently of ILS. On the other hand, 10-HDA did not extend the lifespan of the eat-2 mutants, which show long lifespan through dietary restriction caused by a food-intake defect. This finding indicates that 10-HDA extends lifespan through dietary restriction signaling. We further found that 10-HDA did not extend the lifespan of the long-lived mutants in daf-15, which encodes Raptor, a target of rapamycin (TOR) components, indicating that 10-HDA shared some longevity control mechanisms with TOR signaling. Additionally, 10-HDA was found to confer tolerance against thermal and oxidative stress. 10-HDA increases longevity not through ILS but through dietary restriction and TOR signaling in C. elegans.