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Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning.
Cell. 2011 Apr 29; 145(3):383-97
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05 May 2011
New Finding
DOI: 10.3410/f.10149956.10926054
This paper reports the fascinating finding that the ribosome may be regulated in a highly specific and dynamic manner to confer transcript-specific translational control and, consequently, affect different aspects of development.
The authors showed that loss of Ribosomal Protein L38 (Rpl38) in mice does...Continue reading
The authors showed that loss of Ribosomal Protein L38 (Rpl38) in mice does...Continue reading
This paper reports the fascinating finding that the ribosome may be regulated in a highly specific and dynamic manner to confer transcript-specific translational control and, consequently, affect different aspects of development.
The authors showed that loss of Ribosomal Protein L38 (Rpl38) in mice does not affect global protein synthesis but instead affects the translation of a select subset of homeobox mRNAs, leading to tissue specific patterning defects. They further showed that this effect of RPL38 is due to its ability to facilitate the formation of the 80S complex on these mRNAs. Their additional finding that the expression of individual ribosomal proteins (RPs) is dynamically regulated points to a distinct possibility that the novel mechanism is more widely used during development.
The authors showed that loss of Ribosomal Protein L38 (Rpl38) in mice does not affect global protein synthesis but instead affects the translation of a select subset of homeobox mRNAs, leading to tissue specific patterning defects. They further showed that this effect of RPL38 is due to its ability to facilitate the formation of the 80S complex on these mRNAs. Their additional finding that the expression of individual ribosomal proteins (RPs) is dynamically regulated points to a distinct possibility that the novel mechanism is more widely used during development.
Disclosures
None declared
Add Comment
Zhong W: F1000Prime Recommendation of [Kondrashov N et al., Cell 2011, 145(3):383-97]. In F1000Prime, 05 May 2011; DOI: 10.3410/f.10149956.10926054. F1000Prime.com/10149956#eval10926054
17 May 2011
New Finding
DOI: 10.3410/f.10149956.11408054
My long-held prejudice for the uniformity of ribosomes is totally overthrown by this paper, which demonstrates unequivocally that a protein of the 60S ribosomal subunit, Rpl38, is needed ONLY for the translation of a small, specific set of mRNAs, in this case eight of the more than 30 HOX genes in the...Continue reading
My long-held prejudice for the uniformity of ribosomes is totally overthrown by this paper, which demonstrates unequivocally that a protein of the 60S ribosomal subunit, Rpl38, is needed ONLY for the translation of a small, specific set of mRNAs, in this case eight of the more than 30 HOX genes in the mouse.
The authors identify the long-known Ts (tail-short) mutation in the mouse as due to inactivation of the gene encoding ribosomal protein L38, a part of the 60S ribosomal subunit. This mutation leads to numerous developmental abnormalities, particularly in the skeleton. This is not a general effect of mutations in ribosomal protein genes; others lead to effects on total protein synthesis, or effects in other developmental lineages, but not to specific deficits in the translation of these HOX mRNAs. Recreation of the skeletal phenotype by deletion of the appropriate HOX gene(s) gives strong support to the notion that translational regulation by L38 is the key factor missing. The authors point out that L38 is not present in prokaryotic ribosomes, but is found on a large, relatively unstructured, 'expansion segment' of the 28S rRNA that could influence the association of specific mRNAs.
There are two unexpected observations: the mutation is dominant; even with a deficiency of only half of the L38 protein almost none of the mRNA of the affected HOX genes is found in polysomes. Even more startling is the authors' claim that there is a >200-fold variation in the amount of mRNAs for different ribosomal proteins in their survey of a number of developmental tissues. Since each ribosome needs one of each protein, this observation is puzzling indeed!
The authors identify the long-known Ts (tail-short) mutation in the mouse as due to inactivation of the gene encoding ribosomal protein L38, a part of the 60S ribosomal subunit. This mutation leads to numerous developmental abnormalities, particularly in the skeleton. This is not a general effect of mutations in ribosomal protein genes; others lead to effects on total protein synthesis, or effects in other developmental lineages, but not to specific deficits in the translation of these HOX mRNAs. Recreation of the skeletal phenotype by deletion of the appropriate HOX gene(s) gives strong support to the notion that translational regulation by L38 is the key factor missing. The authors point out that L38 is not present in prokaryotic ribosomes, but is found on a large, relatively unstructured, 'expansion segment' of the 28S rRNA that could influence the association of specific mRNAs.
There are two unexpected observations: the mutation is dominant; even with a deficiency of only half of the L38 protein almost none of the mRNA of the affected HOX genes is found in polysomes. Even more startling is the authors' claim that there is a >200-fold variation in the amount of mRNAs for different ribosomal proteins in their survey of a number of developmental tissues. Since each ribosome needs one of each protein, this observation is puzzling indeed!
Disclosures
None declared
Warner J: F1000Prime Recommendation of [Kondrashov N et al., Cell 2011, 145(3):383-97]. In F1000Prime, 17 May 2011; DOI: 10.3410/f.10149956.11408054. F1000Prime.com/10149956#eval11408054
23 May 2011
Patrice Morin
F1000 Genomics & Genetics
National Institute on Aging, National Institutes of Health,
Baltimore, MD, USA.
F1000 Genomics & Genetics
National Institute on Aging, National Institutes of Health,
Baltimore, MD, USA.
Mihee Kim
F1000 Genomics & Genetics
National Institute on Aging, National Institutes of Health,
Baltimore, MD , USA.
F1000 Genomics & Genetics
National Institute on Aging, National Institutes of Health,
Baltimore, MD , USA.
Confirmation, New Finding
DOI: 10.3410/f.10149956.11531059
This paper is remarkable as it shows that a ribosomal protein, which is typically thought of as an abundant constitutive component of the ribosome, can have a regulatory role in tissue patterning during mammalian embryonic development.
The authors of this study take a multi-faceted approach to characterize...Continue reading
The authors of this study take a multi-faceted approach to characterize...Continue reading
This paper is remarkable as it shows that a ribosomal protein, which is typically thought of as an abundant constitutive component of the ribosome, can have a regulatory role in tissue patterning during mammalian embryonic development.
The authors of this study take a multi-faceted approach to characterize multiple mouse mutants with similar developmental abnormalities. They first use a genetic approach to pinpoint RPL38 as the gene that contains the responsible mutations and they confirm this finding by creating a RPL38 knock-in mouse to restore function. They show that while most Hox gene expression is unaffected in the mutant mice, the translation of a subset of these genes is altered, identifying these mRNAs as downstream targets of RPL38 action. The authors are therefore able to make a strong link between mutations in RPL38 and changes in the translation of mRNAs responsible for skeletal/neural-tube patterning in the mouse. While the notion that the ubiquitously expressed ribosomal proteins might play a role in the selectivity of some of the translated mRNAs has been debated for many years, this study is one of the first that demonstrates that a ribosomal protein can indeed have a clear regulatory role. More importantly, the findings raise many interesting questions: what are other non-canonical ribosomal roles for non-assembled ribosomal proteins in the cytoplasm? What are the signature motifs in the target mRNAs that can be recognized by ribosomal proteins under different cellular pressures? In addition, it will also be interesting to identify other ribosomal proteins that might be responsible for selectively enhancing the translation of specific target mRNAs in development or other cellular processes.
The authors of this study take a multi-faceted approach to characterize multiple mouse mutants with similar developmental abnormalities. They first use a genetic approach to pinpoint RPL38 as the gene that contains the responsible mutations and they confirm this finding by creating a RPL38 knock-in mouse to restore function. They show that while most Hox gene expression is unaffected in the mutant mice, the translation of a subset of these genes is altered, identifying these mRNAs as downstream targets of RPL38 action. The authors are therefore able to make a strong link between mutations in RPL38 and changes in the translation of mRNAs responsible for skeletal/neural-tube patterning in the mouse. While the notion that the ubiquitously expressed ribosomal proteins might play a role in the selectivity of some of the translated mRNAs has been debated for many years, this study is one of the first that demonstrates that a ribosomal protein can indeed have a clear regulatory role. More importantly, the findings raise many interesting questions: what are other non-canonical ribosomal roles for non-assembled ribosomal proteins in the cytoplasm? What are the signature motifs in the target mRNAs that can be recognized by ribosomal proteins under different cellular pressures? In addition, it will also be interesting to identify other ribosomal proteins that might be responsible for selectively enhancing the translation of specific target mRNAs in development or other cellular processes.
Disclosures
None declared
Morin P and Kim M: F1000Prime Recommendation of [Kondrashov N et al., Cell 2011, 145(3):383-97]. In F1000Prime, 23 May 2011; DOI: 10.3410/f.10149956.11531059. F1000Prime.com/10149956#eval11531059
25 May 2011
New Finding
DOI: 10.3410/f.10149956.11690057
This paper reveals a new mechanism of regulation of gene expression in mice that uses ribosomal protein L38.
This article by Kondrashov et al. reveals a new way of post-transcriptional regulation of gene expression. The authors found mutations of the large ribosomal subunit protein L38 (Rpl38) gene resulted...Continue reading
This article by Kondrashov et al. reveals a new way of post-transcriptional regulation of gene expression. The authors found mutations of the large ribosomal subunit protein L38 (Rpl38) gene resulted...Continue reading
This paper reveals a new mechanism of regulation of gene expression in mice that uses ribosomal protein L38.
This article by Kondrashov et al. reveals a new way of post-transcriptional regulation of gene expression. The authors found mutations of the large ribosomal subunit protein L38 (Rpl38) gene resulted in tissue-specific patterning defects. The authors showed that mutations of L38 perturb translation of a specific subset of homeobox mRNAs. Moreover, the authors demonstrated significant tissue-specific variations in expression levels of other ribosomal proteins. These findings lead to an intriguing possibility that, in eukaryotes, a subset of ribosomal proteins bind to the ribosomal RNA in a regulated manner creating 'specialized ribosomes', which preferentially translate specific mRNAs. Further studies are required to investigate molecular mechanisms by which ribosomal proteins may regulate translation and recruitment to the ribosome of specific mRNAs.
This article by Kondrashov et al. reveals a new way of post-transcriptional regulation of gene expression. The authors found mutations of the large ribosomal subunit protein L38 (Rpl38) gene resulted in tissue-specific patterning defects. The authors showed that mutations of L38 perturb translation of a specific subset of homeobox mRNAs. Moreover, the authors demonstrated significant tissue-specific variations in expression levels of other ribosomal proteins. These findings lead to an intriguing possibility that, in eukaryotes, a subset of ribosomal proteins bind to the ribosomal RNA in a regulated manner creating 'specialized ribosomes', which preferentially translate specific mRNAs. Further studies are required to investigate molecular mechanisms by which ribosomal proteins may regulate translation and recruitment to the ribosome of specific mRNAs.
Disclosures
None declared
Makhatadze G and Ermolenko D: F1000Prime Recommendation of [Kondrashov N et al., Cell 2011, 145(3):383-97]. In F1000Prime, 25 May 2011; DOI: 10.3410/f.10149956.11690057. F1000Prime.com/10149956#eval11690057
26 May 2011
New Finding
DOI: 10.3410/f.10149956.11728054
This paper reports the surprising observation that ribosomal protein L38, and by inference the ribosome itself, can influence the selection of mRNAs to undergo translation.
In current models of protein synthesis, the ribosome functions solely to catalyze amide bond formation; mRNA selection and the regulation...Continue reading
In current models of protein synthesis, the ribosome functions solely to catalyze amide bond formation; mRNA selection and the regulation...Continue reading
This paper reports the surprising observation that ribosomal protein L38, and by inference the ribosome itself, can influence the selection of mRNAs to undergo translation.
In current models of protein synthesis, the ribosome functions solely to catalyze amide bond formation; mRNA selection and the regulation of initiation, elongation, and termination are mediated by key accessory proteins. Kondrashov and colleagues, however, find that a ribosomal protein, Rpl38, can function in the selection and translation of a specific subset of mRNAs while leaving global translation unchanged. Further, they establish the physiological significance of this phenomenon by observing that embryos expressing mutant forms of Rpl38 display tissue patterning defects.
This work helps to establish a second paradigm for post-transcription regulation in which the ribosome serves not just as a catalyst, but actively selects the mRNAs with which it will interact. Such mechanisms have been proposed {1}, but, prior to this study, little had been done to show that this sort of regulation actually occurs. Should this role for the ribosome prove to be widespread, an entirely novel mode of post-transcriptional regulation will be established.
Mechanistic conclusions from this work, however, should be treated with caution. The authors interpret a reduction in the amount of a target mRNA co-fractionating with the 80S ribosome to mean that the formation of this complex is the step mediated by Rpl38. Several other interpretations of these data are possible, including inhibition of 5' cap recognition by the 40S ribosome.
In current models of protein synthesis, the ribosome functions solely to catalyze amide bond formation; mRNA selection and the regulation of initiation, elongation, and termination are mediated by key accessory proteins. Kondrashov and colleagues, however, find that a ribosomal protein, Rpl38, can function in the selection and translation of a specific subset of mRNAs while leaving global translation unchanged. Further, they establish the physiological significance of this phenomenon by observing that embryos expressing mutant forms of Rpl38 display tissue patterning defects.
This work helps to establish a second paradigm for post-transcription regulation in which the ribosome serves not just as a catalyst, but actively selects the mRNAs with which it will interact. Such mechanisms have been proposed {1}, but, prior to this study, little had been done to show that this sort of regulation actually occurs. Should this role for the ribosome prove to be widespread, an entirely novel mode of post-transcriptional regulation will be established.
Mechanistic conclusions from this work, however, should be treated with caution. The authors interpret a reduction in the amount of a target mRNA co-fractionating with the 80S ribosome to mean that the formation of this complex is the step mediated by Rpl38. Several other interpretations of these data are possible, including inhibition of 5' cap recognition by the 40S ribosome.
References
Disclosures
None declared
Nicchitta C and Reid D: F1000Prime Recommendation of [Kondrashov N et al., Cell 2011, 145(3):383-97]. In F1000Prime, 26 May 2011; DOI: 10.3410/f.10149956.11728054. F1000Prime.com/10149956#eval11728054
01 Jun 2011
Lucio Comai
F1000 Cell Biology
Keck School of Medicine, University of Southern California,
Los Angeles, CA, USA.
F1000 Cell Biology
Keck School of Medicine, University of Southern California,
Los Angeles, CA, USA.
New Finding
DOI: 10.3410/f.10149956.11767054
Not all ribosomes are created equal: this is the message that resonates from this innovative study on the function of the ribosomal protein (RP) L38 in mice, which demonstrates a novel mechanism of control of translation of a set of developmentally regulated mRNAs.
The authors showed that skeletal...Continue reading
The authors showed that skeletal...Continue reading
Not all ribosomes are created equal: this is the message that resonates from this innovative study on the function of the ribosomal protein (RP) L38 in mice, which demonstrates a novel mechanism of control of translation of a set of developmentally regulated mRNAs.
The authors showed that skeletal patterning defects observed in "Tail short" (Ts) mice are caused by mutations in the RPL38 gene. Loss of RPL38 alters the expression of a subset of HOX mRNA without significantly affecting global protein synthesis, suggesting that this ribosomal protein has a specialized role in translation. Indeed, these defects are not observed in mice strains bearing mutations in other ribosomal protein genes. Further analysis points to unique elements in the untranslated region (UTR) sequences of this set of Hox mRNAs as the likely sites for the regulation of translation by RPL38. These findings thus reveal a new layer of regulation of tissue-specific gene expression at the post-transcriptional level that until now has gone undetected.
The authors showed that skeletal patterning defects observed in "Tail short" (Ts) mice are caused by mutations in the RPL38 gene. Loss of RPL38 alters the expression of a subset of HOX mRNA without significantly affecting global protein synthesis, suggesting that this ribosomal protein has a specialized role in translation. Indeed, these defects are not observed in mice strains bearing mutations in other ribosomal protein genes. Further analysis points to unique elements in the untranslated region (UTR) sequences of this set of Hox mRNAs as the likely sites for the regulation of translation by RPL38. These findings thus reveal a new layer of regulation of tissue-specific gene expression at the post-transcriptional level that until now has gone undetected.
Disclosures
None declared
Comai L: F1000Prime Recommendation of [Kondrashov N et al., Cell 2011, 145(3):383-97]. In F1000Prime, 01 Jun 2011; DOI: 10.3410/f.10149956.11767054. F1000Prime.com/10149956#eval11767054
24 Jun 2011
New Finding
DOI: 10.3410/f.10149956.12558056
This is a fascinating discovery about a single ribosomal protein Rpl38 that controls tissue patterning by specifically regulating gene expression of a subset of Hox genes.
The ribosome is famous for its role as a macromolecular machine in protein synthesis. However, in recent years there is growing evidence...Continue reading
The ribosome is famous for its role as a macromolecular machine in protein synthesis. However, in recent years there is growing evidence...Continue reading
This is a fascinating discovery about a single ribosomal protein Rpl38 that controls tissue patterning by specifically regulating gene expression of a subset of Hox genes.
The ribosome is famous for its role as a macromolecular machine in protein synthesis. However, in recent years there is growing evidence showing that individual ribosomal proteins have functional specificity in different species such as yeast, plants, and fish. This article further affirmed the idea of functional specificity of individual ribosomal proteins. Additionally, the authors demonstrated that a single ribosomal protein Rpl38 is required for efficient translation of a subset of Hox genes by facilitating 80S-mRNA formation, thereby regulating skeletal patterning during embryogenesis. But, how exactly Rpl38 achieves this gene specific translation regulation needs further investigation. Another striking finding in this article is that most ribosomal proteins show distinct tissue expression patterns in the mouse embryo, implicating the importance of individual ribosomal proteins during development.
The ribosome is famous for its role as a macromolecular machine in protein synthesis. However, in recent years there is growing evidence showing that individual ribosomal proteins have functional specificity in different species such as yeast, plants, and fish. This article further affirmed the idea of functional specificity of individual ribosomal proteins. Additionally, the authors demonstrated that a single ribosomal protein Rpl38 is required for efficient translation of a subset of Hox genes by facilitating 80S-mRNA formation, thereby regulating skeletal patterning during embryogenesis. But, how exactly Rpl38 achieves this gene specific translation regulation needs further investigation. Another striking finding in this article is that most ribosomal proteins show distinct tissue expression patterns in the mouse embryo, implicating the importance of individual ribosomal proteins during development.
Disclosures
None declared
Marcotte E and Li Z: F1000Prime Recommendation of [Kondrashov N et al., Cell 2011, 145(3):383-97]. In F1000Prime, 24 Jun 2011; DOI: 10.3410/f.10149956.12558056. F1000Prime.com/10149956#eval12558056
F1000Prime Recommendations, Dissents and Comments for [Kondrashov N et al., Cell 2011, 145(3):383-97]. In F1000Prime, 24 May 2013; F1000Prime.com/10149956
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Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than regulatory capacity in mRNA translation. Here we identify mutations of the Ribosomal Protein L38 (Rpl38) gene in mice exhibiting surprising tissue-specific patterning defects, including pronounced homeotic transformations of the axial skeleton. In Rpl38 mutant embryos, global protein synthesis is unchanged; however the translation of a select subset of Homeobox mRNAs is perturbed. Our data reveal that RPL38 facilitates 80S complex formation on these mRNAs as a regulatory component of the ribosome to confer transcript-specific translational control. We further show that Rpl38 expression is markedly enriched in regions of the embryo where loss-of-function phenotypes occur. Unexpectedly, a ribosomal protein (RP) expression screen reveals dynamic regulation of individual RPs within the vertebrate embryo. Collectively, these findings suggest that RP activity may be highly regulated to impart a new layer of specificity in the control of gene expression and mammalian development.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2011.03.028
PMID: 21529712
