Genetic Resolutions of Brain Convolutions Brian G. Rash and Pasko Rakic Science 343, 744 (2014); DOI: 10.1126/science.1250246
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Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
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PERSPECTIVES faces, effectively forming the core of the protein and extending to the ice-binding surface (see the figure, panel B). Sun et al. show that the structure determined from crystallography persists in solution as the active form of the protein. Although ordered water molecules can be detected in most high-resolution x-ray crystallographic structures, they are usually located between replica molecules in the crystal lattice and are probably absent or quite rare when the protein is in native solution conditions, in contrast to the water inside Maxi. That the ordered water structure in Maxi extends to the ice-binding surface is suggestive of the function of this unusual core, given that Maxi, as an antifreeze protein, must bind ice nuclei and inhibit their growth to function. As Sun et al. suggest, this function may have driven the evolution of its unique water core, although clearly such a core is not necessary for antifreeze activity. No other known antifreeze protein has a water core like Maxi’s. When a protein folds, it forms van der Waals (packing) interactions, hydrogen bonds, and electrostatic interactions between charged and polar side chains within the protein. Each of these interactions competes with interactions of comparable strength and number between water and protein in the unfolded state. No such competition exists for the hydrophobic effect:
Entropically favorable release of water upon burying apolar groups unambiguously favors the folded state. Thus, it is widely accepted that stabilization of globular proteins occurs primarily through the hydrophobic effect (8). It is therefore startling that Maxi retains the very structure of water—“semi-clathrate” in the words of Sun et al.—whose formation around apolar groups and subsequent disappearance was deemed to be the hallmark of the hydrophobic effect (5) and pivotal for protein stabilization. Clearly, the balance of interactions that stabilize Maxi is quite different from that used by most proteins. Maxi’s structure has intriguing implications not only for the energetics of protein folding, but for the mechanism and kinetics as well. Examination of the anhydrous core of any protein with its convoluted but well-packed atom-atom interfaces (see the figure, panel A) raises the question of how the water is removed so efficiently during folding. Removal of this water has been proposed as a potential rate-limiting step in protein folding. Two competing mechanisms have been proposed: Either the water is driven out as the protein collapses, or the unfavorable hydration free energy of apolar groups leads to their spontaneous dewetting (9). In the first mechanism, protein packing drives dehydration in the manner of a squeegee, whereas in the second, packing follows dehydration.
Resolution of this question depends on the relative magnitudes of packing and hydration forces, which have proved difficult to determine by experiment or theory. Moreover, proteins may well use both mechanisms. But it seems Maxi did not get the memo on how to fold: It chooses neither route to dehydration. Maxi folds to the point where water not in direct contact with the protein chain is removed from its core. It then arrests further folding to retain a beautifully ordered core of water interleaved between the protein helices. Further analysis of the energetics and kinetics of folding of Maxi will deepen our understanding of protein folding and stabilization. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
J. C. Kendrew et al., Nature 181, 662 (1958). H. M. Berman et al., Nucleic Acids Res. 28, 235 (2000). F. M. Richards, J. Mol. Biol. 82, 1 (1974). T. Sun, F.-H. Lin, R. L. Campbell, J. S. Allingham, P. L. Davies, Science 343, 795 (2014). W. Kauzmann, Adv. Protein Chem. 14, 1 (1959). C. H. Tanford, The Hydrophobic Effect (Wiley, New York, 1973). R. Henderson et al., J. Mol. Biol. 213, 899 (1990). K. A. Dill, Biochem. 29, 7133 (1990). Y. Levy, J. N. Onuchic, Annu. Rev. Biophys. Biomol. Struct. 35, 389 (2006). M. Ambrazi et al., Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 64, 432 (2008). W. L. DeLano, PyMOL Molecular Graphics System (DeLano Scientific, San Carlos, CA, 2002).
10.1126/science.1249405
NEUROSCIENCE
Genetic Resolutions of Brain Convolutions
Genetic analysis of human brain abnormalities aids our understanding of how the cerebral cortex develops and evolves.
Brian G. Rash1 and Pasko Rakic1, 2
C
ortical convolutions—prominent folds on the surface of the human brain—have a long history of speculation (1). The claims range from their function as a bodily cooling system to the attribution of Einstein’s genius to the unusual shape of a single gyrus (the ridge of a cortical fold). Only recently, with advances in molecular genetics and brain imaging techniques, has it become possible to study the development, evolution, and abnormalities of cerebral convolutions in a scientifically 1
Department of Neurobiology, Yale University, New Haven, CT 06510, USA. 2Kavli Institute for Neuroscience, Yale University, New Haven, CT 06510, USA. E-mail pasko.rakic@ yale.edu
744
rigorous manner (2). On page 764 of this issue, Bae et al. (3) show that a specific gene controls the number of gyri that form in a region of the cerebral cortex that includes Broca’s area (the major language area). This begins to pinpoint mechanisms that underlie the development of specialized regions of the human brain and may be relevant to understanding human brain evolution. Bae et al. examined individuals, from three consanguineous families, with abnormal cortical folding restricted to a region surrounding the Sylvian fissure, including Broca’s area within the frontal lobe. Through a genome-wide linkage analysis, the authors traced the abnormality to mutations in the noncoding regulatory region of
the GPR56 gene. GPR56 encodes a protein that functions in cell adhesion and guidance. Mutations caused the peri-Sylvian cortex to be thinner and smoother and exhibit multiple shallow indentations (polymicrogyria). Moreover, the authors discovered a natural, spontaneous mutation in the GPR56 locus, which points to a mechanism that underlies both the formation of cortical maps and the process of gyrification. Bae et al. generated transgenic mice in which different expression patterns of a reporter gene (encoding β-galactosidase) could be driven by part of the noncoding region of GPR56 (a minimal promoter) taken from human, marmoset, dolphin, cat, and mouse. This indicates evolutionary changes in cortical
14 FEBRUARY 2014 VOL 343 SCIENCE www.sciencemag.org Published by AAAS
PERSPECTIVES the mechanisms of protomap patterning or the subsequent formation of abnormal connections (GPR56 mutation) requires further investigation. Preplate The study by Bae et al. raises Subventricular zone (SVZ) questions about how new conVentricular zone (VZ) Adjacent Peri-Sylvian Adjacent volutions and even new cortical areas area areas lobes can be created during evolution by simple genomic mutaB Midgestational stage tions (2). That areas and gyri can be modified or created at will in the laboratory by altering a single 1 gene or factor that controls mor4 5 Cortical plate 6 GPR56 expression. Overexpresphogenesis provides insight into Outer SVZ SVZ sion of GPR56 in mice increased the possible mechanisms of corVZ proliferation of neuroprogenitor tical development (6–10, 12, 13), cells in the cortex, whereas loss but whether such experimentally of GPR56 expression had the induced changes are biologiopposite effect. cally useful is another question. C Postmigratory stage The results of Bae et al. are Bae et al. have shown that a sinpredictable by the radial unit gle gene mutation can reconfighypothesis and related protomap ure the cortex in a functionally hypothesis, which concern the deleterious manner, but through 1 2 formation of the cortical areas evolution, such a mutation may 3 Cortex 4 5 and convolutions. These concepts prove to be advantageous for the 6 have framed our current undersurvival of species. The GPR56 White matter standing of the development and promoter can drive gene expresNormal gyri Abnormal peri-Sylvian Normal gyri evolution of cortical areas and sion in the lateral cortex in nongyrification their convolutions in the context human species, indicating that it of the genetic regulation of prois important, but not sufficient, liferation and migration of newborn neurons cells) at early stages will add radial units and to create a new area such as Broca’s, so the into columns within the overlying cortical enlarge the surface area for that population search for the decisive gene(s) should conplate (4). The models explain why the cor- compared to the rest of the cortical primor- tinue. The study by Bae et al. demonstrates tex normally expands not as a lump or glob- dium. By contrast, a local decrease in pro- the potential of using advanced methods in ular nucleus (such as the striatum or thala- liferation at early stages would diminish the human to identify specific genes and test mus), but as a relatively uniform thin, flat cortical surface, and if continued at later their function in animals in order to obtain sheet composed of an array of radial units. stages, would also decrease cortical thick- information on the origin of human uniqueBecause the ventricular zone (VZ) of the ness (see the figure). The results of Bae et ness (2, 14, 15). cerebral cortex produces deep layers, and al., in which both VZ and SVZ are involved, References and Notes the subventricular zone (SVZ) produces are predictable by these models and support 1. S. Gould, The Mismeasure of Man (Norton, New York, neurons destined mostly for the superficial the idea that cortical size and its foldings 1996). layers, both zones must be equally engaged are an extended property of local cell pro2. D. H. Geschwind, P. Rakic, Neuron 80, 633 (2013). 3. B.-I. Bae et al., Science 343, 764 (2014). in this complex process (5) (see the figure). liferation in the transient embryonic zones. 4. P. Rakic, Nat. Rev. Neurosci. 10, 724 (2009). The horizontal constraints provided by the The grossly distorted and disorganized cor5. R. F. Hevner, T. F. Haydar, Cereb. Cortex 22, 465 (2012). radial glial cell scaffolding, which is so tical columns observed by Bae et al. could 6. T. Fukuchi-Shimogori, E. A. Grove, Science 294, 1071 prominent in the gyrencephalic brains of be attributed to the abnormal shape of radial (2001). 7. J. A. Cholfin, J. L. Rubenstein, J. Comp. Neurol. 509, 144 human and nonhuman primates, explains glial cells, some of which lose their attach(2008). why the larger cortex became convoluted ments to the pial surface (the thin membrane 8. D. D. O’Leary, D. Borngasser, Cereb. Cortex 16 (suppl. 1), and forms primary, and initiates secondary, that surrounds the brain). i46 (2006). 9. P. Rakic, Science 241, 170 (1988). furrows (sulci) on the brain’s surface even After the protomap is established, the before birth (2, 4). final pattern of gyri in each area is probably 10. B. G. Rash, S. Tomasi, H. D. Lim, C. Y. Suh, F. M. Vaccarino, J. Neurosci. 33, 10802 (2013). Animal studies have shown that the size a product of both differential cellular prolif- 11. D. C. Van Essen, Nature 385, 313 (1997). and position of various cortical areas can eration and subsequent formation of connec- 12. A. Chenn, C. A. Walsh, Science 297, 365 (2002). be manipulated in a region-specific man- tions during cortical maturation (11). Bae et 13. T. F. Haydar, C. Y. Kuan, R. A. Flavell, P. Rakic, Cereb. Cortex 9, 621 (1999). ner by molecules that control morphogene- al. show that gyrification in human cortex 14. G. Clowry, Z. Molnár, P. Rakic, J. Anat. 217, 276 (2010). sis (6–10), indicating that the pattern of the is a regional event controlled by local pro- 15. K. Y. Kwan et al., Cell 149, 899 (2012). primordial cortical protomap is malleable at liferation that starts at early stages, before : We thank A. Ayoub and J. Arellano for early embryonic stages. Mechanistically, for the initiation of neuronal connections (2, 4). Acknowledgments helpful discussion. B.G.R. and P.R. are supported by NIH grants example, a local increase in the prolifera- This supports the existence of mechanisms DA023999 and NS014841. tive rate of a prepatterned regional popula- that locally regulate gyrification, but the 10.1126/science.1250246 tion of radial glial cells (cortical neural stem extent to which they are intermingled with
CREDIT: ADAPTED BY V. ALTOUNIAN/SCIENCE
Localized gyral abnormalities. (A) Early embryonic stage in an individual with the GPR56 mutation showing the prospective areas surrounding the Sylvian fissure (red) and adjacent cortex (blue) within the indicated zones. (B) Middle stage of corticogenesis indicating the prospective normal and affected peri-Sylvian cortical areas. (C) Postmigratory stage, showing abnormal gyrification and cytoarchitecture in the periSylvian region flanked by normal cortical areas.
A Early gestational stage
www.sciencemag.org SCIENCE VOL 343 14 FEBRUARY 2014 Published by AAAS
745
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of February 13, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/343/6172/744.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/343/6172/744.full.html#related This article cites 14 articles, 8 of which can be accessed free: http://www.sciencemag.org/content/343/6172/744.full.html#ref-list-1
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on February 14, 2014
This copy is for your personal, non-commercial use only.
PERSPECTIVES faces, effectively forming the core of the protein and extending to the ice-binding surface (see the figure, panel B). Sun et al. show that the structure determined from crystallography persists in solution as the active form of the protein. Although ordered water molecules can be detected in most high-resolution x-ray crystallographic structures, they are usually located between replica molecules in the crystal lattice and are probably absent or quite rare when the protein is in native solution conditions, in contrast to the water inside Maxi. That the ordered water structure in Maxi extends to the ice-binding surface is suggestive of the function of this unusual core, given that Maxi, as an antifreeze protein, must bind ice nuclei and inhibit their growth to function. As Sun et al. suggest, this function may have driven the evolution of its unique water core, although clearly such a core is not necessary for antifreeze activity. No other known antifreeze protein has a water core like Maxi’s. When a protein folds, it forms van der Waals (packing) interactions, hydrogen bonds, and electrostatic interactions between charged and polar side chains within the protein. Each of these interactions competes with interactions of comparable strength and number between water and protein in the unfolded state. No such competition exists for the hydrophobic effect:
Entropically favorable release of water upon burying apolar groups unambiguously favors the folded state. Thus, it is widely accepted that stabilization of globular proteins occurs primarily through the hydrophobic effect (8). It is therefore startling that Maxi retains the very structure of water—“semi-clathrate” in the words of Sun et al.—whose formation around apolar groups and subsequent disappearance was deemed to be the hallmark of the hydrophobic effect (5) and pivotal for protein stabilization. Clearly, the balance of interactions that stabilize Maxi is quite different from that used by most proteins. Maxi’s structure has intriguing implications not only for the energetics of protein folding, but for the mechanism and kinetics as well. Examination of the anhydrous core of any protein with its convoluted but well-packed atom-atom interfaces (see the figure, panel A) raises the question of how the water is removed so efficiently during folding. Removal of this water has been proposed as a potential rate-limiting step in protein folding. Two competing mechanisms have been proposed: Either the water is driven out as the protein collapses, or the unfavorable hydration free energy of apolar groups leads to their spontaneous dewetting (9). In the first mechanism, protein packing drives dehydration in the manner of a squeegee, whereas in the second, packing follows dehydration.
Resolution of this question depends on the relative magnitudes of packing and hydration forces, which have proved difficult to determine by experiment or theory. Moreover, proteins may well use both mechanisms. But it seems Maxi did not get the memo on how to fold: It chooses neither route to dehydration. Maxi folds to the point where water not in direct contact with the protein chain is removed from its core. It then arrests further folding to retain a beautifully ordered core of water interleaved between the protein helices. Further analysis of the energetics and kinetics of folding of Maxi will deepen our understanding of protein folding and stabilization. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
J. C. Kendrew et al., Nature 181, 662 (1958). H. M. Berman et al., Nucleic Acids Res. 28, 235 (2000). F. M. Richards, J. Mol. Biol. 82, 1 (1974). T. Sun, F.-H. Lin, R. L. Campbell, J. S. Allingham, P. L. Davies, Science 343, 795 (2014). W. Kauzmann, Adv. Protein Chem. 14, 1 (1959). C. H. Tanford, The Hydrophobic Effect (Wiley, New York, 1973). R. Henderson et al., J. Mol. Biol. 213, 899 (1990). K. A. Dill, Biochem. 29, 7133 (1990). Y. Levy, J. N. Onuchic, Annu. Rev. Biophys. Biomol. Struct. 35, 389 (2006). M. Ambrazi et al., Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 64, 432 (2008). W. L. DeLano, PyMOL Molecular Graphics System (DeLano Scientific, San Carlos, CA, 2002).
10.1126/science.1249405
NEUROSCIENCE
Genetic Resolutions of Brain Convolutions
Genetic analysis of human brain abnormalities aids our understanding of how the cerebral cortex develops and evolves.
Brian G. Rash1 and Pasko Rakic1, 2
C
ortical convolutions—prominent folds on the surface of the human brain—have a long history of speculation (1). The claims range from their function as a bodily cooling system to the attribution of Einstein’s genius to the unusual shape of a single gyrus (the ridge of a cortical fold). Only recently, with advances in molecular genetics and brain imaging techniques, has it become possible to study the development, evolution, and abnormalities of cerebral convolutions in a scientifically 1
Department of Neurobiology, Yale University, New Haven, CT 06510, USA. 2Kavli Institute for Neuroscience, Yale University, New Haven, CT 06510, USA. E-mail pasko.rakic@ yale.edu
744
rigorous manner (2). On page 764 of this issue, Bae et al. (3) show that a specific gene controls the number of gyri that form in a region of the cerebral cortex that includes Broca’s area (the major language area). This begins to pinpoint mechanisms that underlie the development of specialized regions of the human brain and may be relevant to understanding human brain evolution. Bae et al. examined individuals, from three consanguineous families, with abnormal cortical folding restricted to a region surrounding the Sylvian fissure, including Broca’s area within the frontal lobe. Through a genome-wide linkage analysis, the authors traced the abnormality to mutations in the noncoding regulatory region of
the GPR56 gene. GPR56 encodes a protein that functions in cell adhesion and guidance. Mutations caused the peri-Sylvian cortex to be thinner and smoother and exhibit multiple shallow indentations (polymicrogyria). Moreover, the authors discovered a natural, spontaneous mutation in the GPR56 locus, which points to a mechanism that underlies both the formation of cortical maps and the process of gyrification. Bae et al. generated transgenic mice in which different expression patterns of a reporter gene (encoding β-galactosidase) could be driven by part of the noncoding region of GPR56 (a minimal promoter) taken from human, marmoset, dolphin, cat, and mouse. This indicates evolutionary changes in cortical
14 FEBRUARY 2014 VOL 343 SCIENCE www.sciencemag.org Published by AAAS
PERSPECTIVES the mechanisms of protomap patterning or the subsequent formation of abnormal connections (GPR56 mutation) requires further investigation. Preplate The study by Bae et al. raises Subventricular zone (SVZ) questions about how new conVentricular zone (VZ) Adjacent Peri-Sylvian Adjacent volutions and even new cortical areas area areas lobes can be created during evolution by simple genomic mutaB Midgestational stage tions (2). That areas and gyri can be modified or created at will in the laboratory by altering a single 1 gene or factor that controls mor4 5 Cortical plate 6 GPR56 expression. Overexpresphogenesis provides insight into Outer SVZ SVZ sion of GPR56 in mice increased the possible mechanisms of corVZ proliferation of neuroprogenitor tical development (6–10, 12, 13), cells in the cortex, whereas loss but whether such experimentally of GPR56 expression had the induced changes are biologiopposite effect. cally useful is another question. C Postmigratory stage The results of Bae et al. are Bae et al. have shown that a sinpredictable by the radial unit gle gene mutation can reconfighypothesis and related protomap ure the cortex in a functionally hypothesis, which concern the deleterious manner, but through 1 2 formation of the cortical areas evolution, such a mutation may 3 Cortex 4 5 and convolutions. These concepts prove to be advantageous for the 6 have framed our current undersurvival of species. The GPR56 White matter standing of the development and promoter can drive gene expresNormal gyri Abnormal peri-Sylvian Normal gyri evolution of cortical areas and sion in the lateral cortex in nongyrification their convolutions in the context human species, indicating that it of the genetic regulation of prois important, but not sufficient, liferation and migration of newborn neurons cells) at early stages will add radial units and to create a new area such as Broca’s, so the into columns within the overlying cortical enlarge the surface area for that population search for the decisive gene(s) should conplate (4). The models explain why the cor- compared to the rest of the cortical primor- tinue. The study by Bae et al. demonstrates tex normally expands not as a lump or glob- dium. By contrast, a local decrease in pro- the potential of using advanced methods in ular nucleus (such as the striatum or thala- liferation at early stages would diminish the human to identify specific genes and test mus), but as a relatively uniform thin, flat cortical surface, and if continued at later their function in animals in order to obtain sheet composed of an array of radial units. stages, would also decrease cortical thick- information on the origin of human uniqueBecause the ventricular zone (VZ) of the ness (see the figure). The results of Bae et ness (2, 14, 15). cerebral cortex produces deep layers, and al., in which both VZ and SVZ are involved, References and Notes the subventricular zone (SVZ) produces are predictable by these models and support 1. S. Gould, The Mismeasure of Man (Norton, New York, neurons destined mostly for the superficial the idea that cortical size and its foldings 1996). layers, both zones must be equally engaged are an extended property of local cell pro2. D. H. Geschwind, P. Rakic, Neuron 80, 633 (2013). 3. B.-I. Bae et al., Science 343, 764 (2014). in this complex process (5) (see the figure). liferation in the transient embryonic zones. 4. P. Rakic, Nat. Rev. Neurosci. 10, 724 (2009). The horizontal constraints provided by the The grossly distorted and disorganized cor5. R. F. Hevner, T. F. Haydar, Cereb. Cortex 22, 465 (2012). radial glial cell scaffolding, which is so tical columns observed by Bae et al. could 6. T. Fukuchi-Shimogori, E. A. Grove, Science 294, 1071 prominent in the gyrencephalic brains of be attributed to the abnormal shape of radial (2001). 7. J. A. Cholfin, J. L. Rubenstein, J. Comp. Neurol. 509, 144 human and nonhuman primates, explains glial cells, some of which lose their attach(2008). why the larger cortex became convoluted ments to the pial surface (the thin membrane 8. D. D. O’Leary, D. Borngasser, Cereb. Cortex 16 (suppl. 1), and forms primary, and initiates secondary, that surrounds the brain). i46 (2006). 9. P. Rakic, Science 241, 170 (1988). furrows (sulci) on the brain’s surface even After the protomap is established, the before birth (2, 4). final pattern of gyri in each area is probably 10. B. G. Rash, S. Tomasi, H. D. Lim, C. Y. Suh, F. M. Vaccarino, J. Neurosci. 33, 10802 (2013). Animal studies have shown that the size a product of both differential cellular prolif- 11. D. C. Van Essen, Nature 385, 313 (1997). and position of various cortical areas can eration and subsequent formation of connec- 12. A. Chenn, C. A. Walsh, Science 297, 365 (2002). be manipulated in a region-specific man- tions during cortical maturation (11). Bae et 13. T. F. Haydar, C. Y. Kuan, R. A. Flavell, P. Rakic, Cereb. Cortex 9, 621 (1999). ner by molecules that control morphogene- al. show that gyrification in human cortex 14. G. Clowry, Z. Molnár, P. Rakic, J. Anat. 217, 276 (2010). sis (6–10), indicating that the pattern of the is a regional event controlled by local pro- 15. K. Y. Kwan et al., Cell 149, 899 (2012). primordial cortical protomap is malleable at liferation that starts at early stages, before : We thank A. Ayoub and J. Arellano for early embryonic stages. Mechanistically, for the initiation of neuronal connections (2, 4). Acknowledgments helpful discussion. B.G.R. and P.R. are supported by NIH grants example, a local increase in the prolifera- This supports the existence of mechanisms DA023999 and NS014841. tive rate of a prepatterned regional popula- that locally regulate gyrification, but the 10.1126/science.1250246 tion of radial glial cells (cortical neural stem extent to which they are intermingled with
CREDIT: ADAPTED BY V. ALTOUNIAN/SCIENCE
Localized gyral abnormalities. (A) Early embryonic stage in an individual with the GPR56 mutation showing the prospective areas surrounding the Sylvian fissure (red) and adjacent cortex (blue) within the indicated zones. (B) Middle stage of corticogenesis indicating the prospective normal and affected peri-Sylvian cortical areas. (C) Postmigratory stage, showing abnormal gyrification and cytoarchitecture in the periSylvian region flanked by normal cortical areas.
A Early gestational stage
www.sciencemag.org SCIENCE VOL 343 14 FEBRUARY 2014 Published by AAAS
745
