Germ Cell Migration in Zebrafish Is Dependent on HMGCoA Reductase Activity and Prenylation

Thorpe, Juanita L.; Doitsidou, Maria; Ho, Shiu-Ying; Raz, Eraz; Farber, Steven A.

doi:10.1016/s1534-5807(04)00032-2

Cited by 103 publications

(98 citation statements)

References 23 publications

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“…1B), and so we predicted that inhibition of HMG-CoA reductase would eliminate the MGC increase in opa3 ZM/ZM mutants. Treatment of zebrafish embryos with the HMG-CoA reductase inhibitor simvastatin caused a shortened body axis, which we could prevent by co-incubation with mevalonate, as reported by others (Thorpe et al, 2004). We saw no phenotypic differences between simvastatin-treated opa3 +/+ embryos and opa3 ZM/ZM mutants (data not shown).…”

Section: Evidence For An Hmg Salvage Pathway Downstream Of Extra-mitosupporting

confidence: 82%

A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3

et al. 2010

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SUMMARYCosteff Syndrome, which is caused by mutations in the OPTIC ATROPHY 3 (OPA3) gene, is an early-onset syndrome characterized by urinary excretion of 3-methylglutaconic acid (MGC), optic atrophy and movement disorders, including ataxia and extrapyramidal dysfunction. The OPA3 protein is enriched in the inner mitochondrial membrane and has mitochondrial targeting signals, but a requirement for mitochondrial localization has not been demonstrated. We find zebrafish opa3 mRNA to be expressed in the optic nerve and retinal layers, the counterparts of which in humans have high mitochondrial activity. Transcripts of zebrafish opa3 are also expressed in the embryonic brain, inner ear, heart, liver, intestine and swim bladder. We isolated a zebrafish opa3 null allele for which homozygous mutants display increased MGC levels, optic nerve deficits, ataxia and an extrapyramidal movement disorder. This correspondence of metabolic, ophthalmologic and movement abnormalities between humans and zebrafish demonstrates a phylogenetic conservation of OPA3 function. We also find that delivery of exogenous Opa3 can reduce increased MGC levels in opa3 mutants, and this reduction requires the mitochondrial localization signals of Opa3. By manipulating MGC precursor availability, we infer that elevated MGC in opa3 mutants derives from extra-mitochondrial HMGCoA through a non-canonical pathway. The opa3 mutants have normal mitochondrial oxidative phosphorylation profiles, but are nonetheless sensitive to inhibitors of the electron transport chain, which supports clinical recommendations that individuals with Costeff Syndrome avoid mitochondria-damaging agents. In summary, this paper introduces a faithful Costeff Syndrome model and demonstrates a requirement for mitochondrial OPA3 to limit HMG-CoA-derived MGC and protect the electron transport chain against inhibitory compounds.

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Section: Evidence For An Hmg Salvage Pathway Downstream Of Extra-mitosupporting

confidence: 82%

A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3

et al. 2010

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“…This would not be surprising because germline precursors often arise far from the somatic gonad and a common feature of germline cells in many species is chemoattractant-guided migration through mesodermal epithelia to the gonad (Kunwar et al, 2006). In Danio (Thorpe et al, 2004) and Drosophila (Santos and Lehmann, 2004), the chemoattractants are lipid modified peptides. In Drosophila the lipid modified peptides are secreted by an ABCB-transporter (Mdr49) expressed in the somatic gonad, but not in the germ cells, presumably because it would interfere with the reception of the chemoattractant.…”

Section: Discussionmentioning

confidence: 99%

Programmed reduction of ABC transporter activity in sea urchin germline progenitors

Campanale

Hamdoun

2012

Development

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There was an error published in Development 139, 783-792.The left and right designations were inadvertently switched in Fig. 7. In Fig. 7C, the y-axis should refer to the right, not left, coelomic pouch. The corrected Fig. 7 legend is shown below. In addition, on p. 789 (lines 46 and 50) and p. 790 (line 58), where a 3/5 left-right distribution is referred to, the correct designation should be 5/3 left-right. The authors apologise to readers for this mistake.

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“…We first analyzed embryos mutant in the gene that encodes the upstream, rate-limiting biosynthetic enzyme HMG-CoA reductase b (Hmgcrb). Hmgcr activity is required for primordial germ cell migration and heart morphogenesis in Drosophila, mice and zebrafish (Van Doren et al, 1998;Thorpe et al, 2004;Yi et al, 2006;D'Amico et al, 2007;Ding et al, 2008). In comparison to wild-type (WT) and Pk1bMO embryos (Fig.…”

Section: A Mutation In the Pk1b Farnesylation Motif Blocks Fbmn Migramentioning

confidence: 98%

Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity

et al. 2011

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SUMMARYThe facial branchiomotor neurons (FBMNs) undergo a characteristic tangential migration in the vertebrate hindbrain. We previously used a morpholino knockdown approach to reveal that zebrafish prickle1b (pk1b) is required for this migration. Here we report that FBMN migration is also blocked in a pk1b mutant with a disruption in the consensus farnesylation motif. We confirmed that this lipid modification is required during FBMN migration by disrupting the function of farnesyl biosynthetic enzymes. Furthermore, farnesylation of a tagged Pk1b is required for its nuclear localization. Using a unique rescue approach, we have demonstrated that Pk1b nuclear localization and farnesylation are required during FBMN migration. Our data suggest that Pk1b acts at least partially independently of core planar cell polarity molecules at the plasma membrane, and might instead be acting at the nucleus. We also found that the neuronal transcriptional silencer REST is necessary for FBMN migration, and we provide evidence that interaction between Pk1b and REST is required during this process. Finally, we demonstrate that REST protein, which is normally localized in the nuclei of migrating FBMNs, is depleted from the nuclei of Pk1b-deficient neurons. We conclude that farnesylation-dependent nuclear localization of Pk1b is required to regulate REST localization and thus FBMN migration.

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Germ Cell Migration in Zebrafish Is Dependent on HMGCoA Reductase Activity and Prenylation

Cited by 103 publications

References 23 publications

A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3

A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3

Programmed reduction of ABC transporter activity in sea urchin germline progenitors

Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity

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