A transgenic monkey model for the study of human brain evolution

2019·0.23 MB·

by  Shi, Lei

ZOOLOGICAL RESEARCH
controls. Furthermore, the transgenic monkeys had more Clark AG, Glanowski S, Nielsen R, Thomas PD, Kejariwal A, Todd MA,
immature and fewer mature neurons and glial cells than the TanenbaumDM,CivelloD,LuF,MurphyB,FerrieraS,WangG,ZhengX,
controls, which, according to the transcriptome data, was White TJ, Sninsky JJ, Adams MD, Cargill M. 2003. Inferring nonneutral
likely caused by the suppression of many neuron maturation- evolution from human-chimp-mouse orthologous gene trios. Science,
and neuron differentiation-related genes. This observation 302(5652):1960–1963.
A transgenic monkey model for the study of human
was further illustrated by detailed analysis of developing brain Coors ME, Glover JJ, Juengst ET, Sikela JM. 2010. The ethics of using
laminasattheneurogenesispeakduringfetaldevelopment.
transgenic non-human primates to study what makes us human. Nature
brain evolution
Finally, to test whether the observed delay in brain
ReviewsGenetics,11(9):658–662.
development had any impact on behavior and cognition, we
Enard W, Gehre S, Hammerschmidt K, Hölter SM, Blass T, Somel M,
tested working memory in the transgenic monkeys using
BrücknerMK,SchreiweisC,WinterC,SohrR,BeckerL,WiebeV,NickelB,
delayed matching-to-sample tasks. Notably, the transgenic
LeiShi1,2,BingSu1,2,3,* GigerT,MüllerU,GroszerM,AdlerT,AguilarA,BolleI,Calzada-WackJ,
monkeys exhibited better working memory and shorter
Dalke C, Ehrhardt N, Favor J, Fuchs H, Gailus-Durner V, Hans W,
1State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming reaction time than the controls, suggesting that neotenous
Hölzlwimmer G, Javaheri A, Kalaydjiev S, Kallnik M, Kling E, Kunder S,
Yunnan650223,China brain development in the transgenic monkeys was beneficial
MossbruggerI,NatonB,RaczI,RathkolbB,RozmanJ,SchreweA,Busch
2PrimateResearchCenter,KunmingInstituteofZoology,ChineseAcademyofSciences,KunmingYunnan650223,China fortheformationofcognitiveabilities,confirmingtheproposed
3CenterforExcellenceinAnimalEvolutionandGenetics,ChineseAcademyofSciences,KunmingYunnan650223,China evolutionary advantage of human neoteny. In our future work, DH, Graw J, Ivandic B, Klingenspor M, KlopstockT, Ollert M, Quintanilla-
we will: (1) examine the molecular pathway explaining how MartinezL,SchulzH,WolfE,WurstW,ZimmerA,FisherSE,Morgenstern
human MCPH1 copies delay brain development and neural R, Arendt T, de Angelis MH, Fischer J, Schwarz J, Pääbo S. 2009. A
maturation, thus identifying more neoteny-related genes; and humanized version of Foxp2 affects cortico-basal ganglia circuits in mice.
Why humans have large brains with higher cognitive abilities Zhang et al., 2014), yet relatively large phylogenetic distance
(2) apply more sophisticated tests to further understand how Cell,137(5):961–971.
isaquestionlongaskedbyscientists.However,muchremains (~25millionyearsofdivergencefromhumans),whichalleviates
the neotenous brain affects cognitive formation in transgenic Gruber R, Zhou Z, Sukchev M, Joerss T, Frappart PO,Wang ZQ. 2011.
unknown,especiallytheunderlyinggeneticmechanisms.With certainethicalconcerns(Coorsetal.,2010).Theseadvantages
monkeys. MCPH1 regulates the neuroprogenitor division mode by coupling the
the use of a transgenic monkey model, we showed that have been demonstrated in the use of transgenic monkey
Thisstudyrepresentsthefirstattempttoutilizeatransgenic centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway.
human-specificsequencechangesofakeybraindevelopment modelsofhumandiseases(Chenetal.,2017;Liuetal.,2016;
monkeymodeltostudyhumanbrainevolution.Italsoprovides NatureCellBiology,13(11):1325–1334.
gene(Primarymicrocephaly1,MCPH1)couldresultindetectable Luo et al., 2016; Qiu et al., 2019;Yang et al., 2008; Zhang et
the first molecular genetic evidence showing neotenous JacksonAP,EastwoodH,BellSM,AduJ,ToomesC,CarrIM,RobertsE,
molecularandcognitivechangesresemblinghumanneoteny,a al.,2018).
notablecharacteristicdevelopedduringhumanevolution.This MCPH1isakeygeneregulatingbraindevelopmentinhumans, changes during brain development caused by human-specific HampshireDJ,CrowYJ,MighellAJ,KarbaniG,JafriH,RashidY,Mueller
mutations of a single gene. The results highlight the great
study was published in National Science Review (Shi et al., and its truncate mutations can cause primary microcephaly RF,MarkhamAF,WoodsCG.2002.Identificationofmicrocephalin,aprotein
potential of non-human primate models in studying human
2019). (Jacksonetal.,2002).Similarly,MCPH1knockoutinmiceand implicatedindeterminingthesizeofthehumanbrain.AmericanJournalof
evolution and may pave the way for future studies to explore
Neoteny has been hypothesized to help explain why we monkeyscanrecapitulatethemicrocephalyphenotype(Gruber HumanGenetics,71(1):136–142.
thegeneticmechanismsofhuman-specifictraitsandelucidate
differ from our close relatives, such as the chimpanzee (Pan et al., 2011; Ke et al., 2016), highlighting its critical role in KeQ,LiW,LaiX,ChenH,HuangL,KangZ,LiK,RenJ,LinX,ZhengH,
the etiology of human brain disorders such as autism and
troglodytes) (Liu et al., 2012). Also called juvenilization, mammalian brain development. In previous research, we HuangW,MaY,XuD,ChenZ,SongX,LinX,ZhuangM,WangT,Zhuang
Alzheimer’sdisease.
neoteny is the delay in or slowing down of physiological demonstratedacceleratedproteinsequencechangesinMCPH1 F,XiJ,MaoFF,XiaH,LahnBT,ZhouQ,YangS,XiangAP.2016.TALEN-
developmentofaspecies(Skulachevetal.,2015).Neotenyin during primate evolution, especially in the lineage leading to based generation of a cynomolgus monkey disease model for human
COMPETINGINTERESTS
humansistheretentionofjuvenilefeaturesintoadulthoodandis theoriginofourownspecies(Wang&Su,2004).Furthermore, microcephaly.CellResearch,26(9):1048–1061.
exaggerated compared to that in non-human primates. The invitrofunctionalanalysisshowedthathuman-specificMCPH1 LiuX,SomelM,TangL,YanZ,JiangX,GuoS,YuanY,HeL,OleksiakA,
neotenous human brain provides an extended window for the changes resulted in functional divergence between human Theauthorsdeclarethattheyhavenocompetinginterests. Zhang Y, Li N, Hu Y, Chen W, Qiu Z, Paabo S, Khaitovich P. 2012.
plasticity of the neural network,andthereforealongertimefor and non-human primates (Shi et al., 2013). Such lines of Extension of cortical synaptic development distinguishes humans from
learning, which may be crucial for the formation of human evidence raise the question as to what phenotypic changes AUTHORS’CONTRIBUTIONS
chimpanzeesandmacaques.GenomeResearch,22(4):611–622.
cognition(Bufilletal.,2011). would appear following the introduction of human MCPH1
LiuZ,LiX,ZhangJT,CaiYJ,ChengTJ,ChengC,WangY,ZhangCC,Nie
Inthepasttwodecades,comparativegenomicstudieshave copiesintotherhesusmonkeygenome. L.S.andB.S.wrotethemanuscript.Allauthorsreadandapprovedthefinal
YH,ChenZF,BianWJ,ZhangL,XiaoJ,LuB,ZhangYF,ZhangXD,Sang
identified many candidate genes that carry human-specific Using lentivirus delivery, we successfully generated 11 versionofthemanuscript.
X,WuJJ,XuX,XiongZQ,ZhangF,YuX,GongN,ZhouWH,SunQ,Qiu
sequence changes potentially contributing to human brain transgenic monkeys carrying 2–9 copies of human MCPH1.
evolution(Bustamanteetal.,2005;Clarketal.,2003).However, Brain image analysis showed that the transgenic monkeys REFERENCES Z. 2016. Autism-like behaviours and germline transmission in transgenic
functionaldissectionofthesecandidategenes,particularlythe hadsimilarbrainvolumeandcortexthicknessasthecontrols, monkeysoverexpressingMeCP2.Nature,530(7588):98–102.
phenotypic consequences of human-specific mutations, is but their relative brain volume and gray matter percentage Bufill E,Agustí J, Blesa R. 2011. Human neoteny revisited: The case of LuoX,LiM,SuB.2016.ApplicationofthegenomeeditingtoolCRISPR/
lacking.Asamodelorganism,transgenicmice(Musmusculus) were higher. Importantly, the transgenic monkeys exhibited synapticplasticity.AmericanJournalofHumanBiology,23(6):729–739. Cas9innon-humanprimates.ZoologicalResearch,37(4):214–219.
have been used in the study of human brain function; for delayed cortex gray matter development compared to the Bustamante CD, Fledel-Alon A, Williamson S, Nielsen R, Hubisz MT, QiuP,JiangJ,LiuZ,CaiY,HuangT,WangY,LiuQ,NieY,LiuF,ChengJ,
example, the study of Foxp2 that carries two human-specific Glanowski S, Tanenbaum DM, White TJ, Sninsky JJ, Hernandez RD, Li Q, Tang YC, Poo MM, Sun Q, Chang HC. 2019. BMAL1 knockout
amino acid changes (Enard et al., 2009). However, compared Civello D, Adams MD, Cargill M, Clark AG. 2005. Natural selection on macaque monkeys display reduced sleep and psychiatric disorders.
tothehumanbrain,themousebrainisdramaticallydifferentin Received:04April2019;Accepted:09April2019;Online:11April2019 protein-codinggenesinthehumangenome.Nature,437(7062):1153–1157. NationalScienceReview,6(1):87–100.
size, structure, developmental pattern, and function, and Foundation items: This study was supported by the Strategic Priority ChenY,YuJ,NiuY,QinD,LiuH,LiG,HuY,WangJ,LuY,KangY,Jiang ShiL,LiM,LinQ,QiX,SuB.2013.Functionaldivergenceofthebrain-size
thereforeisnotanidealmodeltostudyhumanbrainevolution. Research Program of the Chinese Academy of Sciences Y,WuK,LiS,WeiJ,HeJ,WangJ,LiuX,LuoY,SiC,BaiR,ZhangK,Liu regulatinggeneMCPH1duringprimateevolutionandtheoriginofhumans.
In contrast, the rhesus monkey (Macaca mulatta), an Old- (XDB13000000), the National Natural Science Foundation of China J, Huang S, Chen Z, Wang S, Chen X, Bao X, Zhang Q, Li F, Geng R, BMCBiology,11:62.
World primate species widely used in biomedical research, is (31730088)andtheYouthInnovationPromotionAssociationofCAS LiangA,ShenD,JiangT,HuX,MaY,JiW,SunY.E.2017.Modelingrett ShiL,LuoX,JiangJ,ChenY,LiuC,HuT,LiM,LinQ,LiY,HuangJ,Wang
a better animal model due to its high sequence similarity with *Correspondingauthor,E-mail:[email protected] syndromeusingTALEN-EditedMECP2mutantcynomolgusmonkeys.Cell, H,NiuY,ShiY,StynerM,WangJ,LuY,SunX,YuH,JiW,SuB.2019.
humans (>93% for protein coding genes) (Yan et al., 2011; DOI:10.24272/j.issn.2095-8137.2019.031 169(5):945–955. TransgenicrhesusmonkeyscarryingthehumanMCPH1genecopiesshow
236 SciencePress ZoologicalResearch 40(3):236 238,2019
-
controls. Furthermore, the transgenic monkeys had more Clark AG, Glanowski S, Nielsen R, Thomas PD, Kejariwal A, Todd MA,
immature and fewer mature neurons and glial cells than the TanenbaumDM,CivelloD,LuF,MurphyB,FerrieraS,WangG,ZhengX,
controls, which, according to the transcriptome data, was White TJ, Sninsky JJ, Adams MD, Cargill M. 2003. Inferring nonneutral
likely caused by the suppression of many neuron maturation- evolution from human-chimp-mouse orthologous gene trios. Science,
and neuron differentiation-related genes. This observation 302(5652):1960–1963.
was further illustrated by detailed analysis of developing brain Coors ME, Glover JJ, Juengst ET, Sikela JM. 2010. The ethics of using
laminasattheneurogenesispeakduringfetaldevelopment.
transgenic non-human primates to study what makes us human. Nature
Finally, to test whether the observed delay in brain
ReviewsGenetics,11(9):658–662.
development had any impact on behavior and cognition, we
Enard W, Gehre S, Hammerschmidt K, Hölter SM, Blass T, Somel M,
tested working memory in the transgenic monkeys using
BrücknerMK,SchreiweisC,WinterC,SohrR,BeckerL,WiebeV,NickelB,
delayed matching-to-sample tasks. Notably, the transgenic
GigerT,MüllerU,GroszerM,AdlerT,AguilarA,BolleI,Calzada-WackJ,
monkeys exhibited better working memory and shorter
Dalke C, Ehrhardt N, Favor J, Fuchs H, Gailus-Durner V, Hans W,
reaction time than the controls, suggesting that neotenous
Hölzlwimmer G, Javaheri A, Kalaydjiev S, Kallnik M, Kling E, Kunder S,
brain development in the transgenic monkeys was beneficial
MossbruggerI,NatonB,RaczI,RathkolbB,RozmanJ,SchreweA,Busch
fortheformationofcognitiveabilities,confirmingtheproposed
evolutionary advantage of human neoteny. In our future work, DH, Graw J, Ivandic B, Klingenspor M, KlopstockT, Ollert M, Quintanilla-
we will: (1) examine the molecular pathway explaining how MartinezL,SchulzH,WolfE,WurstW,ZimmerA,FisherSE,Morgenstern
human MCPH1 copies delay brain development and neural R, Arendt T, de Angelis MH, Fischer J, Schwarz J, Pääbo S. 2009. A
maturation, thus identifying more neoteny-related genes; and humanized version of Foxp2 affects cortico-basal ganglia circuits in mice.
(2) apply more sophisticated tests to further understand how Cell,137(5):961–971.
the neotenous brain affects cognitive formation in transgenic Gruber R, Zhou Z, Sukchev M, Joerss T, Frappart PO,Wang ZQ. 2011.
monkeys. MCPH1 regulates the neuroprogenitor division mode by coupling the
Thisstudyrepresentsthefirstattempttoutilizeatransgenic centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway.
monkeymodeltostudyhumanbrainevolution.Italsoprovides NatureCellBiology,13(11):1325–1334.
the first molecular genetic evidence showing neotenous JacksonAP,EastwoodH,BellSM,AduJ,ToomesC,CarrIM,RobertsE,
changes during brain development caused by human-specific HampshireDJ,CrowYJ,MighellAJ,KarbaniG,JafriH,RashidY,Mueller
mutations of a single gene. The results highlight the great
RF,MarkhamAF,WoodsCG.2002.Identificationofmicrocephalin,aprotein
potential of non-human primate models in studying human
implicatedindeterminingthesizeofthehumanbrain.AmericanJournalof
evolution and may pave the way for future studies to explore
HumanGenetics,71(1):136–142.
thegeneticmechanismsofhuman-specifictraitsandelucidate
KeQ,LiW,LaiX,ChenH,HuangL,KangZ,LiK,RenJ,LinX,ZhengH,
the etiology of human brain disorders such as autism and
HuangW,MaY,XuD,ChenZ,SongX,LinX,ZhuangM,WangT,Zhuang
Alzheimer’sdisease.
F,XiJ,MaoFF,XiaH,LahnBT,ZhouQ,YangS,XiangAP.2016.TALEN-
based generation of a cynomolgus monkey disease model for human
COMPETINGINTERESTS
microcephaly.CellResearch,26(9):1048–1061.
LiuX,SomelM,TangL,YanZ,JiangX,GuoS,YuanY,HeL,OleksiakA,
Theauthorsdeclarethattheyhavenocompetinginterests.
Zhang Y, Li N, Hu Y, Chen W, Qiu Z, Paabo S, Khaitovich P. 2012.
Extension of cortical synaptic development distinguishes humans from
AUTHORS’CONTRIBUTIONS
chimpanzeesandmacaques.GenomeResearch,22(4):611–622.
LiuZ,LiX,ZhangJT,CaiYJ,ChengTJ,ChengC,WangY,ZhangCC,Nie
L.S.andB.S.wrotethemanuscript.Allauthorsreadandapprovedthefinal
YH,ChenZF,BianWJ,ZhangL,XiaoJ,LuB,ZhangYF,ZhangXD,Sang
versionofthemanuscript.
X,WuJJ,XuX,XiongZQ,ZhangF,YuX,GongN,ZhouWH,SunQ,Qiu
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monkeysoverexpressingMeCP2.Nature,530(7588):98–102.
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synapticplasticity.AmericanJournalofHumanBiology,23(6):729–739. Cas9innon-humanprimates.ZoologicalResearch,37(4):214–219.
Bustamante CD, Fledel-Alon A, Williamson S, Nielsen R, Hubisz MT, QiuP,JiangJ,LiuZ,CaiY,HuangT,WangY,LiuQ,NieY,LiuF,ChengJ,
Glanowski S, Tanenbaum DM, White TJ, Sninsky JJ, Hernandez RD, Li Q, Tang YC, Poo MM, Sun Q, Chang HC. 2019. BMAL1 knockout
Civello D, Adams MD, Cargill M, Clark AG. 2005. Natural selection on macaque monkeys display reduced sleep and psychiatric disorders.
protein-codinggenesinthehumangenome.Nature,437(7062):1153–1157. NationalScienceReview,6(1):87–100.
ChenY,YuJ,NiuY,QinD,LiuH,LiG,HuY,WangJ,LuY,KangY,Jiang ShiL,LiM,LinQ,QiX,SuB.2013.Functionaldivergenceofthebrain-size
Y,WuK,LiS,WeiJ,HeJ,WangJ,LiuX,LuoY,SiC,BaiR,ZhangK,Liu regulatinggeneMCPH1duringprimateevolutionandtheoriginofhumans.
J, Huang S, Chen Z, Wang S, Chen X, Bao X, Zhang Q, Li F, Geng R, BMCBiology,11:62.
LiangA,ShenD,JiangT,HuX,MaY,JiW,SunY.E.2017.Modelingrett ShiL,LuoX,JiangJ,ChenY,LiuC,HuT,LiM,LinQ,LiY,HuangJ,Wang
syndromeusingTALEN-EditedMECP2mutantcynomolgusmonkeys.Cell, H,NiuY,ShiY,StynerM,WangJ,LuY,SunX,YuH,JiW,SuB.2019.
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