npg
© 2015 Nature America, Inc. All rights reserved.
news and views Such reverse segregants make up the major proportion of chromosome segregation errors (8.7%). The majority of these events result in euploid embryos, but with the oocyte and PB2 containing non-sister chromatids and PB1 containing two non-sister chromatids. Such incidences would not result in copy number alterations and so would be unlikely to be identified by array CGH. The authors report different incidences of this phenomenon, but interestingly the chromosomes involved are those that are frequently associated with trisomies or abnormal gametes in IVF clinics (chromosomes 4, 9, 11, 13, 14, 15, 16, 19, 21 and 22). They argue that this novel segregation pattern is not due to two distinct PSSC events at meiosis I and meiosis II. However, it is possible that the altered distribution and frequency of recombination events, particularly at the centromere, may interfere with centromere separation and/ or the attachment of sister chromatids to the same spindle at meiosis I, with both resulting
in sister chromatid segregation rather than the expected homolog segregation. Taken together, these studies have elucidated and, in some cases, confirmed many current theories about the origins of human aneuploidy, particularly those that involve cohesion-mediated events. At the same time, although these studies reinforce the importance of regulating the distribution and frequency of crossover events during prophase I, they suggest that altered recombination frequency may not by itself be responsible for meiosis I non-disjunction events leading to aneuploidy. Instead, these data suggest the importance of accurate recombination distribution to facilitate appropriate sequential release of cohesion. Whether reverse segregation is simply one sequela of altered sister chromatid cohesion or whether it relates instead to altered kinetochore behavior, perhaps resulting from increased recombination at the centro mere, remains to be seen. Either way, these novel findings force us to reexamine the relationship
between recombination and segregation events involving the centromere. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Hassold, T. & Hunt, P. Nat. Rev. Genet. 2, 280–291 (2001). 2. Nagaoka, S.I., Hassold, T.J. & Hunt, P.A. Nat. Rev. Genet. 13, 493–504 (2012). 3. Pratto, F. et al. Science 346, 1256442 (2014). 4. Hou, Y. et al. Cell 155, 1492–1506 (2013). 5. Otollini, C.S. et al. Nat. Genet. 47, 727–735 (2015). 6. Lenzi, M.L. et al. Am. J. Hum. Genet. 76, 112–127 (2005). 7. Suja, J.A. & Barbero, J.L. Genome Dyn. 5, 94–116 (2009). 8. Prieto, I. et al. Chromosome Res. 12, 197–213 (2004). 9. Garcia-Cruz, R. et al. Hum. Reprod. 25, 2316–2327 (2010). 10. Jessberger, R. EMBO Rep. 13, 539–546 (2012). 11. Tease, C., Hartshorne, G.M. & Hulten, M.A. Am. J. Hum. Genet. 70, 1469–1479 (2002). 12. Cabral, G., Marques, A., Schubert, V., Pedrosa-Harand, A. & Schlogelhofer, P. Nat. Commun. 5, 5070 (2014). 13. Heckmann, S. et al. Nat. Commun. 5, 4979 (2014).
Sweet size control in tomato Andrew Fleming All cells of an adult plant are ultimately derived from divisions that occur in small groups of cells distributed throughout the plant, termed meristems. A new study shows that carbohydrate post-translational modification of a peptide signal influences meristem and, as a consequence, fruit size in tomato. Understanding control of the number, distribution and rate of cell divisions in meristems is key to comprehending plant growth and development. In the shoot apical meristem, from which all above-ground plant mass is derived, a conserved molecular module for the maintenance of cell division has been established1,2. At the heart of this module is a homeodomain transcription factor, WUSCHEL (WUS), which acts to promote cell division at the core of the meristem. In response to WUS activity, cells at the periphery of the WUS-expressing region generate a small-peptide signal, CLAVATA3 (CLV3), which feeds back to the inner cells to repress WUS gene expression. This loop constitutes a homeostatic mechanism by which any increase in WUS expression (tending to promote cell division in the meristem) leads to increased CLV3 expression, which represses WUS Andrew Fleming is at the Department of Animal and Plant Sciences, University of Sheffield, Sheffield, UK. e-mail: [email protected]
698
expression, returning cell division to its previous rate. The report by Zachary Lippman and colleagues in this issue3 demonstrates that a post-translational modification of the CLV3 peptide is required for its signaling activity. This modification involves the addition of a triplet of arabinose sugars to a hydroxyproline residue within the peptide. Bearing in mind the important role that carbohydrate modifications have in cell wall structure and function4,5, the finding that the activity of a signaling molecule repressing cell division depends on carbohydrate modification identifies a novel potential interface within plant growth and development. Moreover, the link shown in this study between meristem and fruit size highlights the importance of our understanding of fundamental plant biology for advances in agronomy. Arabinosylation and signal activity Working with tomato, Xu et al.3 identified a series of mutants that had enlarged fruit as a consequence of increased meristem size. Unexpectedly, a number of the underlying
mutations (fin, fab2 and rra3a) affected genes encoding glycosyltransferases, in particular ones associated with the addition of arabinose to proline- or hydroxyproline-rich proteins, such as the cell wall protein extensin4. Although various lines of evidence had already suggested that such post-translational modifications are important in plants6, the mechanisms underpinning links to phenotype have been obscure. For example, loss-of-function mutants in Arabidopsis thaliana that have impaired activity of a series of hydroxyproline O-arabinosyltransferases6 show pleiotropic phenotypes related to growth, such as altered hypocotyl expansion and decreased cell wall thickness. Potential endogenous substrates for these enzymes (including CLV-related proteins) were identified, but a link to growth control was not shown. Xu et al.3 observed that the enlarged meristems in the new tomato mutants are reminiscent of those seen in WUS-CLV pathway mutants, so they looked more closely to determine whether arabinosylation might have a role in the CLV signaling pathway, as
volume 47 | number 7 | JULY 2015 | nature genetics
news and views Arabinosyltransferase
npg
© 2015 Nature America, Inc. All rights reserved.
CLV3
CLV3
Figure 1 The addition of sugars (triple-arabinosyl modification) to a hydroxyproline residue in the CLV3 signal peptide by arabinosyltransferases is required for the repression of meristem growth. Loss of enzyme activity leads to the synthesis of non-modified CLV3, an increase in meristem size and larger fruit.
indeed had previously been postulated7. Their data clearly show that it does. Most convincingly, exogenous supply of synthesized CLV3 peptide with a triarabinoside side chain was far more effective in restoring meristem size in the arabinosyltransferase mutants than the non-arabinosylated peptide. Addition of the arabinosylated CLV3 peptide to a mutant unable to perceive the CLV signal owing to loss of receptor function (fab) did not restore a normal meristem phenotype. The authors went on to identify a series of other genes linking various steps in the established CLV3 signaling
pathway to the control of meristem size in tomato, establishing that the arabinosyl-CLV3 signaling system has a major role in setting meristem size. Because increased meristem size in tomato flowers is linked to an increased number of carpels (from which the fruit form), it leads to an increase in fruit size (Fig. 1). From peptide to produce This work provides a significant advance in our understanding of the importance of post-translational modifications in plant signaling. Although peptide signals have long been known to have a vital role in animal growth and development, for a long time, evidence of their function in plants was less convincing. This has now changed, and the present work adds to the realization of the importance of peptide signals in a variety of plant patterning and growth processes8–10. The involvement of carbohydrates in posttranslational modifications of at least some of these signals11 raises interesting (but as yet mainly untested) possibilities of links between the cell wall, growth and division. In plants, cell division provides the building blocks for future growth, but the final extent of growth is heavily dependent on the mechanical properties of the cell wall12. In addition to structural carbohydrate polymers (for example, for cellulose and pectins), the cell wall contains many proteins that can undergo carbohydrate post-translational modification (including arabinosylation), but the function of these proteins often remains unclear or debatable13,14. Potential crosstalk via carbohydrate modification of signaling molecules and structural protein elements in the cell wall would provide a
novel mechanism for coordinating cell division and growth. It will also be fascinating to see to what extent the activity of other peptide signals in plants is dependent on similar posttranslational modifications11. Finally, it seems that variation of at least one of the CLV3 genes in tomato (at the FAS locus) has been selected during breeding and domestication for cultivars with increased fruit size. This finding highlights the potential for further exploitation of the regulation of meristem size and number for agronomic improvement15, either as a trait for selection or via targeted genetic modification. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. 1. Schoof, H. et al. Cell 100, 635–644 (2000). 2. Fletcher, J.C., Brand, U., Running, M.P., Simon, R. & Meyerowitz, E.M. Science 283, 1911–1914 (1999). 3. Xu, C. et al. Nat. Genet. 47, 784–792 (2015). 4. Lamport, D.T., Kieliszewski, M.J., Chen, Y. & Cannon, M.C. Plant Physiol. 156, 11–19 (2011). 5. Atmodjo, M.A., Hao, Z. & Mohnen, D. Annu. Rev. Plant Biol. 64, 747–779 (2013). 6. Ogawa-Ohnishi, M., Matsushita, W. & Matsubayashi, Y. Nat. Chem. Biol. 9, 726–730 (2013). 7. Ohyama, K., Shinohara, H., Ogawa-Ohnishi, M. & Matsubayashi, Y. Nat. Chem. Biol. 5, 578–580 (2009). 8. Sugano, S.S. et al. Nature 463, 241–244 (2010). 9. Matsuzaki, Y., Ogawa-Ohnishi, M., Mori, A. & Matsubayashi, Y. Science 329, 1065–1067 (2010). 10. Katsir, L., Davies, K.A., Bergmann, D.C. & Laux, T. Curr. Biol. 21, R356–R364 (2011). 11. Matsubayashi, Y. Annu. Rev. Plant Biol. 65, 385–413 (2014). 12. Fleming, A.J. J. Plant Res. 119, 31–36 (2006). 13. Velasquez, S.M. et al. Science 332, 1401–1403 (2011). 14. Ellis, M., Egelund, J., Schultz, C.J. & Bacic, A. Plant Physiol. 153, 403–419 (2010). 15. Park, S.J., Jiang, K., Schatz, M.C. & Lippman, Z.B. Proc. Natl. Acad. Sci. USA 109, 639–644 (2012).
Lipid transport and human brain development Christer Betsholtz How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma. Roughly half of the mammalian brain’s dry weight consists of lipids, making it the second most lipid-rich organ in the body after Christer Betsholtz is in the Vascular Biology Program, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden, and the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. e-mail: [email protected]
adipose tissue. Rather than being used for energy storage, brain lipids are the essential building blocks of cell membranes, which are extremely abundant in the brain, particularly in the vastly arborized neurons and astrocytes and in the myelin sheaths wrapped around axons by oligodendrocytes. How the brain builds and maintains this high lipid content has puzzled researchers. Any transport of lipids from the blood to the brain has to pass the blood-brain barrier (BBB)—the
nature genetics | volume 47 | number 7 | JULY 2015
sealed endothelial surface of the brain’s blood vessels. Additionally, the BBB is thought to be in place before the growth spurts of the mammalian brain and the onset of myelination, which largely take place during the perinatal and juvenile periods. The BBB efficiently blocks the passage of lipoproteins and albumin, the main lipid carriers in the blood. In vivo experiments have also shown that cholesterol and non-essential fatty acids delivered into the blood do not pass into the brain1,2. 699
© 2015 Nature America, Inc. All rights reserved.
news and views Such reverse segregants make up the major proportion of chromosome segregation errors (8.7%). The majority of these events result in euploid embryos, but with the oocyte and PB2 containing non-sister chromatids and PB1 containing two non-sister chromatids. Such incidences would not result in copy number alterations and so would be unlikely to be identified by array CGH. The authors report different incidences of this phenomenon, but interestingly the chromosomes involved are those that are frequently associated with trisomies or abnormal gametes in IVF clinics (chromosomes 4, 9, 11, 13, 14, 15, 16, 19, 21 and 22). They argue that this novel segregation pattern is not due to two distinct PSSC events at meiosis I and meiosis II. However, it is possible that the altered distribution and frequency of recombination events, particularly at the centromere, may interfere with centromere separation and/ or the attachment of sister chromatids to the same spindle at meiosis I, with both resulting
in sister chromatid segregation rather than the expected homolog segregation. Taken together, these studies have elucidated and, in some cases, confirmed many current theories about the origins of human aneuploidy, particularly those that involve cohesion-mediated events. At the same time, although these studies reinforce the importance of regulating the distribution and frequency of crossover events during prophase I, they suggest that altered recombination frequency may not by itself be responsible for meiosis I non-disjunction events leading to aneuploidy. Instead, these data suggest the importance of accurate recombination distribution to facilitate appropriate sequential release of cohesion. Whether reverse segregation is simply one sequela of altered sister chromatid cohesion or whether it relates instead to altered kinetochore behavior, perhaps resulting from increased recombination at the centro mere, remains to be seen. Either way, these novel findings force us to reexamine the relationship
between recombination and segregation events involving the centromere. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Hassold, T. & Hunt, P. Nat. Rev. Genet. 2, 280–291 (2001). 2. Nagaoka, S.I., Hassold, T.J. & Hunt, P.A. Nat. Rev. Genet. 13, 493–504 (2012). 3. Pratto, F. et al. Science 346, 1256442 (2014). 4. Hou, Y. et al. Cell 155, 1492–1506 (2013). 5. Otollini, C.S. et al. Nat. Genet. 47, 727–735 (2015). 6. Lenzi, M.L. et al. Am. J. Hum. Genet. 76, 112–127 (2005). 7. Suja, J.A. & Barbero, J.L. Genome Dyn. 5, 94–116 (2009). 8. Prieto, I. et al. Chromosome Res. 12, 197–213 (2004). 9. Garcia-Cruz, R. et al. Hum. Reprod. 25, 2316–2327 (2010). 10. Jessberger, R. EMBO Rep. 13, 539–546 (2012). 11. Tease, C., Hartshorne, G.M. & Hulten, M.A. Am. J. Hum. Genet. 70, 1469–1479 (2002). 12. Cabral, G., Marques, A., Schubert, V., Pedrosa-Harand, A. & Schlogelhofer, P. Nat. Commun. 5, 5070 (2014). 13. Heckmann, S. et al. Nat. Commun. 5, 4979 (2014).
Sweet size control in tomato Andrew Fleming All cells of an adult plant are ultimately derived from divisions that occur in small groups of cells distributed throughout the plant, termed meristems. A new study shows that carbohydrate post-translational modification of a peptide signal influences meristem and, as a consequence, fruit size in tomato. Understanding control of the number, distribution and rate of cell divisions in meristems is key to comprehending plant growth and development. In the shoot apical meristem, from which all above-ground plant mass is derived, a conserved molecular module for the maintenance of cell division has been established1,2. At the heart of this module is a homeodomain transcription factor, WUSCHEL (WUS), which acts to promote cell division at the core of the meristem. In response to WUS activity, cells at the periphery of the WUS-expressing region generate a small-peptide signal, CLAVATA3 (CLV3), which feeds back to the inner cells to repress WUS gene expression. This loop constitutes a homeostatic mechanism by which any increase in WUS expression (tending to promote cell division in the meristem) leads to increased CLV3 expression, which represses WUS Andrew Fleming is at the Department of Animal and Plant Sciences, University of Sheffield, Sheffield, UK. e-mail: [email protected]
698
expression, returning cell division to its previous rate. The report by Zachary Lippman and colleagues in this issue3 demonstrates that a post-translational modification of the CLV3 peptide is required for its signaling activity. This modification involves the addition of a triplet of arabinose sugars to a hydroxyproline residue within the peptide. Bearing in mind the important role that carbohydrate modifications have in cell wall structure and function4,5, the finding that the activity of a signaling molecule repressing cell division depends on carbohydrate modification identifies a novel potential interface within plant growth and development. Moreover, the link shown in this study between meristem and fruit size highlights the importance of our understanding of fundamental plant biology for advances in agronomy. Arabinosylation and signal activity Working with tomato, Xu et al.3 identified a series of mutants that had enlarged fruit as a consequence of increased meristem size. Unexpectedly, a number of the underlying
mutations (fin, fab2 and rra3a) affected genes encoding glycosyltransferases, in particular ones associated with the addition of arabinose to proline- or hydroxyproline-rich proteins, such as the cell wall protein extensin4. Although various lines of evidence had already suggested that such post-translational modifications are important in plants6, the mechanisms underpinning links to phenotype have been obscure. For example, loss-of-function mutants in Arabidopsis thaliana that have impaired activity of a series of hydroxyproline O-arabinosyltransferases6 show pleiotropic phenotypes related to growth, such as altered hypocotyl expansion and decreased cell wall thickness. Potential endogenous substrates for these enzymes (including CLV-related proteins) were identified, but a link to growth control was not shown. Xu et al.3 observed that the enlarged meristems in the new tomato mutants are reminiscent of those seen in WUS-CLV pathway mutants, so they looked more closely to determine whether arabinosylation might have a role in the CLV signaling pathway, as
volume 47 | number 7 | JULY 2015 | nature genetics
news and views Arabinosyltransferase
npg
© 2015 Nature America, Inc. All rights reserved.
CLV3
CLV3
Figure 1 The addition of sugars (triple-arabinosyl modification) to a hydroxyproline residue in the CLV3 signal peptide by arabinosyltransferases is required for the repression of meristem growth. Loss of enzyme activity leads to the synthesis of non-modified CLV3, an increase in meristem size and larger fruit.
indeed had previously been postulated7. Their data clearly show that it does. Most convincingly, exogenous supply of synthesized CLV3 peptide with a triarabinoside side chain was far more effective in restoring meristem size in the arabinosyltransferase mutants than the non-arabinosylated peptide. Addition of the arabinosylated CLV3 peptide to a mutant unable to perceive the CLV signal owing to loss of receptor function (fab) did not restore a normal meristem phenotype. The authors went on to identify a series of other genes linking various steps in the established CLV3 signaling
pathway to the control of meristem size in tomato, establishing that the arabinosyl-CLV3 signaling system has a major role in setting meristem size. Because increased meristem size in tomato flowers is linked to an increased number of carpels (from which the fruit form), it leads to an increase in fruit size (Fig. 1). From peptide to produce This work provides a significant advance in our understanding of the importance of post-translational modifications in plant signaling. Although peptide signals have long been known to have a vital role in animal growth and development, for a long time, evidence of their function in plants was less convincing. This has now changed, and the present work adds to the realization of the importance of peptide signals in a variety of plant patterning and growth processes8–10. The involvement of carbohydrates in posttranslational modifications of at least some of these signals11 raises interesting (but as yet mainly untested) possibilities of links between the cell wall, growth and division. In plants, cell division provides the building blocks for future growth, but the final extent of growth is heavily dependent on the mechanical properties of the cell wall12. In addition to structural carbohydrate polymers (for example, for cellulose and pectins), the cell wall contains many proteins that can undergo carbohydrate post-translational modification (including arabinosylation), but the function of these proteins often remains unclear or debatable13,14. Potential crosstalk via carbohydrate modification of signaling molecules and structural protein elements in the cell wall would provide a
novel mechanism for coordinating cell division and growth. It will also be fascinating to see to what extent the activity of other peptide signals in plants is dependent on similar posttranslational modifications11. Finally, it seems that variation of at least one of the CLV3 genes in tomato (at the FAS locus) has been selected during breeding and domestication for cultivars with increased fruit size. This finding highlights the potential for further exploitation of the regulation of meristem size and number for agronomic improvement15, either as a trait for selection or via targeted genetic modification. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. 1. Schoof, H. et al. Cell 100, 635–644 (2000). 2. Fletcher, J.C., Brand, U., Running, M.P., Simon, R. & Meyerowitz, E.M. Science 283, 1911–1914 (1999). 3. Xu, C. et al. Nat. Genet. 47, 784–792 (2015). 4. Lamport, D.T., Kieliszewski, M.J., Chen, Y. & Cannon, M.C. Plant Physiol. 156, 11–19 (2011). 5. Atmodjo, M.A., Hao, Z. & Mohnen, D. Annu. Rev. Plant Biol. 64, 747–779 (2013). 6. Ogawa-Ohnishi, M., Matsushita, W. & Matsubayashi, Y. Nat. Chem. Biol. 9, 726–730 (2013). 7. Ohyama, K., Shinohara, H., Ogawa-Ohnishi, M. & Matsubayashi, Y. Nat. Chem. Biol. 5, 578–580 (2009). 8. Sugano, S.S. et al. Nature 463, 241–244 (2010). 9. Matsuzaki, Y., Ogawa-Ohnishi, M., Mori, A. & Matsubayashi, Y. Science 329, 1065–1067 (2010). 10. Katsir, L., Davies, K.A., Bergmann, D.C. & Laux, T. Curr. Biol. 21, R356–R364 (2011). 11. Matsubayashi, Y. Annu. Rev. Plant Biol. 65, 385–413 (2014). 12. Fleming, A.J. J. Plant Res. 119, 31–36 (2006). 13. Velasquez, S.M. et al. Science 332, 1401–1403 (2011). 14. Ellis, M., Egelund, J., Schultz, C.J. & Bacic, A. Plant Physiol. 153, 403–419 (2010). 15. Park, S.J., Jiang, K., Schatz, M.C. & Lippman, Z.B. Proc. Natl. Acad. Sci. USA 109, 639–644 (2012).
Lipid transport and human brain development Christer Betsholtz How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma. Roughly half of the mammalian brain’s dry weight consists of lipids, making it the second most lipid-rich organ in the body after Christer Betsholtz is in the Vascular Biology Program, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden, and the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. e-mail: [email protected]
adipose tissue. Rather than being used for energy storage, brain lipids are the essential building blocks of cell membranes, which are extremely abundant in the brain, particularly in the vastly arborized neurons and astrocytes and in the myelin sheaths wrapped around axons by oligodendrocytes. How the brain builds and maintains this high lipid content has puzzled researchers. Any transport of lipids from the blood to the brain has to pass the blood-brain barrier (BBB)—the
nature genetics | volume 47 | number 7 | JULY 2015
sealed endothelial surface of the brain’s blood vessels. Additionally, the BBB is thought to be in place before the growth spurts of the mammalian brain and the onset of myelination, which largely take place during the perinatal and juvenile periods. The BBB efficiently blocks the passage of lipoproteins and albumin, the main lipid carriers in the blood. In vivo experiments have also shown that cholesterol and non-essential fatty acids delivered into the blood do not pass into the brain1,2. 699
