JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling

Riveiro, Alba Redó; Mariani, Luca; Malmberg, Emily; Amendola, Pier Giorgio; Peltonen, Juhani; Wong, Garry; Salcini, Anna Elisabetta

doi:10.1242/dev.142695

Cited by 16 publications

(22 citation statements)

References 75 publications

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“…Loss of a PHF8 homolog in Caenorhabditis elegans resulted in axon guidance defects via the alteration of Hedgehog-like signaling [ 97 ]. Furthermore, injection of zebrafish PHF8 morpholino caused brain and craniofacial development defects [ 96 ], thus suggested a critical role of histone methylation dynamics regulated by PHF8 in MRXSSD.…”

Section: Neurodevelopmental Disorders Related With Histone Lysine mentioning

confidence: 99%

Histone Lysine Methylation and Neurodevelopmental Disorders

Kim

Lee

et al. 2017

IJMS

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Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases.

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Section: Neurodevelopmental Disorders Related With Histone Lysine mentioning

confidence: 99%

Histone Lysine Methylation and Neurodevelopmental Disorders

Kim

Lee

et al. 2017

IJMS

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“…C. elegans WRT-1 , as expected based on the C terminal similarity to Hh ligands in other organisms, undergoes autoproteolytic cleavage ( Porter et al 1996 ). A handful of studies have investigated specific Hh-related ligands: wrt-5 is essential, and mutants display a variety of morphological defects ( Hao et al 2006a ); and more recently, wrt-8 and grl-16 were implicated in actin remodeling-dependent axon guidance, a role uncovered by their transcriptional up-regulation in jmjd-1.2 mutants ( Riveiro et al 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Functional Interactions Betweenrsks-1/S6K,glp-1/Notch, and Regulators ofCaenorhabditis elegansFertility and Germline Stem Cell Maintenance

Roy

Kahler

Yun

et al. 2018

G3 Genes|Genomes|Genetics

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The proper accumulation and maintenance of stem cells is critical for organ development and homeostasis. The Notch signaling pathway maintains stem cells in diverse organisms and organ systems. In Caenorhabditis elegans, GLP-1/Notch activity prevents germline stem cell (GSC) differentiation. Other signaling mechanisms also influence the maintenance of GSCs, including the highly-conserved TOR substrate ribosomal protein S6 kinase (S6K). Although C. elegans bearing either a null mutation in rsks-1/S6K or a reduction-of-function (rf) mutation in glp-1/Notch produce half the normal number of adult germline progenitors, virtually all these single mutant animals are fertile. However, glp-1(rf) rsks-1(null) double mutant animals are all sterile, and in about half of their gonads, all GSCs differentiate, a distinctive phenotype associated with a significant reduction or loss of GLP-1 signaling. How rsks-1/S6K promotes GSC fate is unknown. Here, we determine that rsks-1/S6K acts germline-autonomously to maintain GSCs, and that it does not act through Cyclin-E or MAP kinase in this role. We found that interfering with translation also enhances glp-1(rf), but that regulation through rsks-1 cannot fully account for this effect. In a genome-scale RNAi screen for genes that act similarly to rsks-1/S6K, we identified 56 RNAi enhancers of glp-1(rf) sterility, many of which were previously not known to interact functionally with Notch. Further investigation revealed at least six candidates that, by genetic criteria, act linearly with rsks-1/S6K. These include genes encoding translation-related proteins, cacn-1/Cactin, an RNA exosome component, and a Hedgehog-related ligand. We found that additional Hedgehog-related ligands may share functional relationships with glp-1/Notch and rsks-1/S6K in maintaining germline progenitors.

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“…To investigate whether jmjd-1 . 2 functions in germ cells, we utilized two deletion alleles: tm3713 carrying a deletion of the PHD domain and zr1010 , a CRISPR-engineered knockout that removes the entire coding sequence 15 . Western blot analysis of wild-type (N2) lysates with a polyclonal antibody against the N-terminus of JMJD-1.2 showed a band of approximately 120 KDa that was absent in mutant lysates (Figs 1a and S1 ), demonstrating the specificity of the antibody for JMJD-1.2.…”

Section: Resultsmentioning

confidence: 99%

“…2 ( tm3713 ) and jmjd-1 . 2 ( zr1010 ) alleles, previously described 15 . We noticed that the jmjd-1 .…”

Section: Methodsmentioning

confidence: 99%

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JMJD-1.2 controls multiple histone post-translational modifications in germ cells and protects the genome from replication stress

Myers

Amendola

Lussi

et al. 2018

Sci Rep

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Post-translational modifications of histones, constitutive components of chromatin, regulate chromatin compaction and control all DNA-based cellular processes. C. elegans JMJD-1.2, a member of the KDM7 family, is a demethylase active towards several lysine residues on Histone 3 (H3), but its contribution in regulating histone methylation in germ cells has not been fully investigated. Here, we show that jmjd-1.2 is expressed abundantly in the germline where it controls the level of histone 3 lysine 9, lysine 23 and lysine 27 di-methylation (H3K9/K23/K27me2) both in mitotic and meiotic cells. Loss of jmjd-1.2 is not associated with major defects in the germ cells in animals grown under normal conditions or after DNA damage induced by UV or ionizing irradiation. However, jmjd-1.2 mutants are more sensitive to replication stress and the progeny of mutant animals exposed to hydroxyurea show increased embryonic lethality and mutational rate, compared to wild-type. Thus, our results suggest a role for jmjd-1.2 in the maintenance of genome integrity after replication stress and emphasize the relevance of the regulation of histone methylation in genomic stability.

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JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling

Cited by 16 publications

References 75 publications

Histone Lysine Methylation and Neurodevelopmental Disorders

Histone Lysine Methylation and Neurodevelopmental Disorders

Functional Interactions Betweenrsks-1/S6K,glp-1/Notch, and Regulators ofCaenorhabditis elegansFertility and Germline Stem Cell Maintenance

JMJD-1.2 controls multiple histone post-translational modifications in germ cells and protects the genome from replication stress

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