Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse

Ding, Jiaxi; Jiang, Dechen; Kurczy, Michael E.; Nalepka, Jennifer; Dudley, Brian; Merkel, Erin; Porter, Forbes D.; Ewing, Andrew G.; Winograd, Nicholas; Burgess, James D.; Molyneaux, Kathleen

doi:10.1186/1471-213x-8-120

Cited by 23 publications

(18 citation statements)

References 44 publications

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“…Finally, there is recent evidence of a role for the Hmgcr pathway in mouse PGC migration (TABLE 2) 95 . Inhibition of Hmgcr in a tissue culture system impairs germ cell migration.…”

Section: Migratory Paths Of Pgcsmentioning

confidence: 99%

Mechanisms guiding primordial germ cell migration: strategies from different organisms

Richardson

Lehmann

2010

Nat Rev Mol Cell Biol

440

417

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Preface The regulated migration of cells is essential for development and tissue homeostasis, and aberrant cell migration can lead to an impaired immune response and the progression of cancer. Primordial germ cells (PGCs), precursors to sperm and eggs, have to migrate across the embryo to reach somatic gonadal precursors (SGPs) and fulfill their function. Studies of model organisms have revealed that, despite important differences, several features of PGC migration are conserved. PGCs require both an intrinsic motility program and external guidance cues to survive and successfully migrate. Proper guidance involves both attractive and repulsive cues mediated by protein and lipid signalling.

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“…Finally, there is recent evidence of a role for the Hmgcr pathway in mouse PGC migration (TABLE 2) 95 . Inhibition of Hmgcr in a tissue culture system impairs germ cell migration.…”

Section: Migratory Paths Of Pgcsmentioning

confidence: 99%

Mechanisms guiding primordial germ cell migration: strategies from different organisms

Richardson

Lehmann

2010

Nat Rev Mol Cell Biol

440

417

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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: 99%

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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“…Fibroblast growth factor (FGF) and BMP signaling molecules are thought to be involved in migration, survival, and proliferation (Takeuchi et al 2005, Dudley et al 2007. A lipid-based system is thought to guide PGC migration in flies (reviewed by Richardson & Lehmann (2010)), and there is evidence for a role of both isoprenoids and cholesterol in PGC migration in vertebrates (Thorpe et al 2004, Ding et al 2008.…”

Section: Migration Of the Pgcsmentioning

confidence: 99%

Sex determination in mammalian germ cells: extrinsic versus intrinsic factors

Bowles

Koopman²

2010

Reproduction

109

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Mammalian germ cells do not determine their sexual fate based on their XX or XY chromosomal constitution. Instead, sexual fate is dependent on the gonadal environment in which they develop. In a fetal testis, germ cells commit to the spermatogenic programme of development during fetal life, although they do not enter meiosis until puberty. In a fetal ovary, germ cells commit to oogenesis by entering prophase of meiosis I. Although it was believed previously that germ cells are pre-programmed to enter meiosis unless they are actively prevented from doing so, recent results indicate that meiosis is triggered by a signaling molecule, retinoic acid (RA). Meiosis is avoided in the fetal testis because a male-specifically expressed enzyme actively degrades RA during the critical time period. Additional extrinsic factors are likely to influence sexual fate of the germ cells, and in particular, we postulate that an additional male-specific fate-determining factor or factors is involved. The full complement of intrinsic factors that underlie the competence of gonadal germ cells to respond to RA and other extrinsic factors is yet to be defined.

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Inhibition of HMG CoA reductase reveals an unexpected role for cholesterol during PGC migration in the mouse

Abstract: Background: Primordial germ cells (PGCs) are the embryonic precursors of the sperm and eggs. Environmental or genetic defects that alter PGC development can impair fertility or cause formation of germ cell tumors.

Cited by 23 publications

References 44 publications

Mechanisms guiding primordial germ cell migration: strategies from different organisms

Mechanisms guiding primordial germ cell migration: strategies from different organisms

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

Sex determination in mammalian germ cells: extrinsic versus intrinsic factors

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