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Antagonism between GLD-2 binding partners controls gamete sex.

ABSTRACT: Cytoplasmic polyadenylation is a key mechanism of gene control. In Caenorhabditis elegans, GLD-2 and GLD-3 provide the catalytic and RNA-binding subunits, respectively, of a major cytoplasmic poly(A) polymerase (PAP). Here, we identify RNP-8 as a second GLD-2 partner. RNP-8 binds GLD-2 and stimulates GLD-2 activity to form a functional PAP, much like GLD-3. Moreover, GLD-2/RNP-8 and GLD-2/GLD-3 exist as separate complexes that form selectively during development, and RNP-8 and GLD-3 appear to have distinct RNA-binding specificities. Therefore, GLD-2 can form either of two discrete PAPs. In C. elegans hermaphrodites, gamete production begins with spermatogenesis and transitions later to oogenesis. We suggest that the combinatorial use of GLD-2 contributes to this transition, as GLD-2/GLD-3 promotes spermatogenesis, whereas GLD-2/RNP-8 specifies oogenesis. Indeed, RNP-8 and GLD-3 antagonize each other, as evidenced by genetic cosuppression and molecular competition for GLD-2 binding. We conclude that GLD-2 and its binding partners control gamete identity.

SUBMITTER: Kim KW

PROVIDER: S-EPMC2728548 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Antagonism between GLD-2 binding partners controls gamete sex.

Kim Kyung Won KW Nykamp Keith K Suh Nayoung N Bachorik Jennifer L JL Wang Liaoteng L Kimble Judith J

Developmental cell 20090501 5

Cytoplasmic polyadenylation is a key mechanism of gene control. In Caenorhabditis elegans, GLD-2 and GLD-3 provide the catalytic and RNA-binding subunits, respectively, of a major cytoplasmic poly(A) polymerase (PAP). Here, we identify RNP-8 as a second GLD-2 partner. RNP-8 binds GLD-2 and stimulates GLD-2 activity to form a functional PAP, much like GLD-3. Moreover, GLD-2/RNP-8 and GLD-2/GLD-3 exist as separate complexes that form selectively during development, and RNP-8 and GLD-3 appear to ha ...[more]

PMID: 19460348

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Project description:Background & aimsβ-catenin is a well-known effector of the Wnt pathway, and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of β-catenin are very frequent in paediatric liver primary tumours. Those mutations are mostly heterozygous, which allows the co-expression of wild-type (WT) and mutated β-catenins in tumour cells. We investigated the interplay between WT and mutated β-catenins in liver tumour cells, and searched for new actors of the β-catenin pathway.MethodsUsing an RNAi strategy in β-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, which are carried mainly by WT and mutated proteins, respectively. Their impact was characterised using transcriptomic and functional analyses. We studied mice that develop liver tumours upon activation of β-catenin in hepatocytes (APCKO and β-cateninΔexon3 mice). We used transcriptomic data from mouse and human HB specimens, and used immunohistochemistry to analyse samples.ResultsWe highlighted an antagonistic role of WT and mutated β-catenins with regard to hepatocyte differentiation, as attested by alterations in the expression of hepatocyte markers and the formation of bile canaliculi. We characterised fascin-1 as a transcriptional target of mutated β-catenin involved in tumour cell differentiation. Using mouse models, we found that fascin-1 is highly expressed in undifferentiated tumours. Finally, we found that fascin-1 is a specific marker of primitive cells including embryonal and blastemal cells in human HBs.ConclusionsFascin-1 expression is linked to a loss of differentiation and polarity of hepatocytes. We present fascin-1 as a previously unrecognised factor in the modulation of hepatocyte differentiation associated with β-catenin pathway alteration in the liver, and as a new potential target in HB.Impact and implicationsThe FSCN1 gene, encoding fascin-1, was reported to be a metastasis-related gene in various cancers. Herein, we uncover its expression in poor-prognosis hepatoblastomas, a paediatric liver cancer. We show that fascin-1 expression is driven by the mutated beta-catenin in liver tumour cells. We provide new insights on the impact of fascin-1 expression on tumour cell differentiation. We highlight fascin-1 as a marker of immature cells in mouse and human hepatoblastomas.

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Antagonism between GLD-2 binding partners controls gamete sex.

Publications

Antagonism between GLD-2 binding partners controls gamete sex.

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