The Immortal Germline

355 Pages·2019·11.711 MB·English

by  Ruth Lehmann

CURRENT TOPICS IN
DEVELOPMENTAL BIOLOGY
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Contributors
LauraChappell
DepartmentofMolecular,Cell,andDevelopmentalBiology,UniversityofCaliforniaSanta
Cruz,SantaCruz,CA,UnitedStates
CuieChen
LifeSciencesInstitute,DepartmentofCellandDevelopmentalBiology,HowardHughes
MedicalInstitute,UniversityofMichigan,AnnArbor,MI,UnitedStates
MelanieIssigonis
RegenerativeBiology,MorgridgeInstituteforResearch,Madison,WI,UnitedStates
AllisonJamieson-Lucy
DepartmentofCellandDevelopmentalBiology,UniversityofPennsylvaniaPerelman
SchoolofMedicine,Philadelphia,PA,UnitedStates
RebeccaG.Jaszczak
DepartmentofObstetrics,GynecologyandReproductiveScience,CenterforReproductive
Sciences,EliandEdytheBroadCenterforRegenerationMedicineandStemCellResearch,
UniversityofCalifornia,SanFrancisco,CA,UnitedStates
KazukiKurimoto
DepartmentofEmbryology,NaraMedicalUniversity,Nara,Japan
DianaJ.Laird
DepartmentofObstetrics,GynecologyandReproductiveScience,CenterforReproductive
Sciences,EliandEdytheBroadCenterforRegenerationMedicineandStemCellResearch,
UniversityofCalifornia,SanFrancisco,CA,UnitedStates
BrianP.Lazzaro
DepartmentsofBiomedicalSciences(SSS),Entomology(BPL),andMolecularBiologyand
Genetics(MFW),CornellUniversity,Ithaca,NY,UnitedStates
MaryC.Mullins
DepartmentofCellandDevelopmentalBiology,UniversityofPennsylvaniaPerelman
SchoolofMedicine,Philadelphia,PA,UnitedStates
JonathanO.Nelson
LifeSciencesInstitute,DepartmentofCellandDevelopmentalBiology,HowardHughes
MedicalInstitute,UniversityofMichigan,AnnArbor,MI,UnitedStates
PhillipA.Newmark
RegenerativeBiology,MorgridgeInstituteforResearch;DepartmentofIntegrativeBiology,
UniversityofWisconsin,Madison,WI;HowardHughesMedicalInstitute,ChevyChase,
MD,UnitedStates
DanielH.Nguyen
DepartmentofObstetrics,GynecologyandReproductiveScience,CenterforReproductive
Sciences,EliandEdytheBroadCenterforRegenerationMedicineandStemCellResearch,
UniversityofCalifornia,SanFrancisco,CA,UnitedStates
ix
x Contributors
TommasoPizzari
EdwardGreyInstitute,DepartmentofZoology,UniversityofOxford,Oxford,
UnitedKingdom
ShelbiL.Russell
DepartmentofMolecular,Cell,andDevelopmentalBiology,UniversityofCaliforniaSanta
Cruz,SantaCruz,CA,UnitedStates
MitinoriSaitou
InstitutefortheAdvancedStudyofHumanBiology(ASHBi);DepartmentofAnatomyand
CellBiology,GraduateSchoolofMedicine;CenterforiPSCellResearchandApplication,
KyotoUniversity,Kyoto,Japan
SusanS.Suarez
DepartmentsofBiomedicalSciences(SSS),Entomology(BPL),andMolecularBiologyand
Genetics(MFW),CornellUniversity,Ithaca,NY,UnitedStates
WilliamSullivan
DepartmentofMolecular,Cell,andDevelopmentalBiology,UniversityofCaliforniaSanta
Cruz,SantaCruz,CA,UnitedStates
M.AzimSurani
WellcomeTrustCancerResearchUKGurdonInstitute;Physiology,Developmentand
NeuroscienceDepartment;WellcomeTrust/MedicalResearchCouncilCambridgeStem
CellInstitute,UniversityofCambridge,Cambridge,UnitedKingdom
AnastasiyaSybirna
WellcomeTrustCancerResearchUKGurdonInstitute;Physiology,Developmentand
NeuroscienceDepartment;WellcomeTrust/MedicalResearchCouncilCambridgeStem
CellInstitute,UniversityofCambridge,Cambridge,UnitedKingdom
StuartWigby
EdwardGreyInstitute,DepartmentofZoology,UniversityofOxford,Oxford,
UnitedKingdom
MarianaF.Wolfner
DepartmentsofBiomedicalSciences(SSS),Entomology(BPL),andMolecularBiologyand
Genetics(MFW),CornellUniversity,Ithaca,NY,UnitedStates
FrederickC.K.Wong
WellcomeTrustCancerResearchUKGurdonInstitute;Physiology,Developmentand
NeuroscienceDepartment,UniversityofCambridge,Cambridge,UnitedKingdom
YukikoM.Yamashita
LifeSciencesInstitute,DepartmentofCellandDevelopmentalBiology,HowardHughes
MedicalInstitute,UniversityofMichigan,AnnArbor,MI,UnitedStates
ShoseiYoshida
DivisionofGermCellBiology,NationalInstituteforBasicBiology,NationalInstitutesof
NaturalSciences;DepartmentofBasicBiology,SchoolofLifeScience,SOKENDAI
(GraduateUniversityforAdvancedStudies),Okazaki,Aichi,Japan
Preface
Germ cells have the sole, yet fundamental task to generate the next gener-
ation.Distinctfromallotherembryoniccellsinthebody,whichcontribute
toparticulartissuesororgans,germcells,dependentonthesexoftheorgan-
ism,willdifferentiateintoeggorsperm.Butforgermcells,differentiationis
notanendpointbutanewbeginning:upontheunionofeggandsperman
entirely new organism will emerge and the cycle can begin anew. The
unique role of germ cells makes them at the same time the safekeepers of
the genetic blueprint of the species to be passed on from generation and
generation, butalsothemediatorsandpropagators ofheritable changethat
is needed for organisms to adapt, evolve, and compete.
Theessaysinthisbookdescribetheintriguingbiologyofgermcellsand
their strategies for transgenerational survival. The germ cell life cycle has
beendescribedingreatdetailinanumberofmodelorganisms,suchasflies,
worms, fishes, frogs, and mice, and most recently in humans. In general,
germ cells acquire their distinct fate during embryogenesis. This can occur
eitherbypreformation,asisfoundinflies,worms,fish,andfrogs,whereby
cellsthatinheritmaternallysynthesizedgermplasmaredestinedtobecome
germ cells, or by induction, as found in mouse, salamanders, and humans,
whereby cell-to-cell signaling instills germ cell fate. Often specified at the
marginoftheembryoproper,germcellshavetomigratetoanewdestina-
tion within the embryo to meet up with the somatic part of the gonad,
which provides important developmental signals and niche function to
the maturing germ cells. Here, germ cells and their somatic support cells
develop according to sexual differentiation cues into testis and ovaries.
In most species, germline stem cells or immature precursor cells exist in
thetestis,whichviaamplificationproducelargeamountsofspermthrough-
out adult life. The existence of germline stem cells in the ovary is rarer
(observed and studied in Drosophila and C. elegans). More commonly
(observedandstudiedinmiceandhumans),thepoolofgermcellsinfemales
is limited. After a period of amplification, early germ cells enter meiosis
and remain arrested at an early differentiated stage of oogenesis for years
or decades to await final maturation. Upon fertilization, the life cycle
begins anew.
Several excellent reviews and collections of germline-centered articles
have been published. The essays in this book summarize some striking,
xi
xii Preface
emerging developments in our understanding of germ cell biology and to
highlight some intriguing aspects of germline development, which
I would like to briefly highlight below.
The oocyte plays a unique part in the development of the organism.
In contrast to sperm, the oocyte does not only provide nuclear, genetic
information to the offspring but also cytoplasm that contains cytoskeletal
specializations and organelles, including mitochondria, which are vital for
embryonic development. In Chapter 1, Mary Mullins and colleagues
describe a granular structure, called the Balbiani body, that is found in
one form or another in the oocytes of species as diverse as flies and mice.
Multiplefunctionshavebeenattributedtothisstillratherobscurestructure,
including roles in oocyte maturation and the establishment of embryonic
polarity but also functions as an organizing center for the germ plasm and
its associated RNAs in animals that specify germ cells by preformation.
Despite its mystery, recent genetic, molecular, and functional dissection
of components in the Balbiani body and other germline-specific
membraneless granules is beginning to reveal common building principles
that may lead to a more mechanistic understanding. Oocytes are also the
preferred passage for endosymbionts to reach the next generation. In
Chapter9,WilliamSullivanandcolleaguesdescribesomeofthefascinating
strategiessymbiontshavechosentoadapttotheirhostandobtainasafepath
for transmission.
Significantprogresshasbeenmadeinidentifyingthemolecularmecha-
nismsleadingtogermcellspecification,whichrequirestheepigeneticreset-
ting of the genome and repression of somatic genes. Indeed, significant
insights have been gained recently through the development of culturing
techniquestostudygermcellspecificationduringearlyhumanembryogen-
esis(AzimSuraniandcolleagues,Chapter2).Acomprehensiveunderstand-
ingofthemolecularframeworkforgermcellspecificationhasmadeitalso
possibletorecapitulatetheprocessinculture.Primordialgermcell-likecells
can now be derived from human and mouse pluripotent stem cells and,
together with gonadal somatic cells, can be prodded toward differentiation
in culture (Chapter 3, Mitinori Saitou and colleagues). Fundamental
principles of germ cells specification can also be gained by “newer” model
systemssuchasplanarians,whicharewell-knownfortheirawesomepoten-
tialtoregenerateacompleteflatwormfromtinycuttingsoftheirformerself.
IntheplanarianSchmidteamediterranea,bothsexualandasexualstrainsexist.
In Chapter 4, Phillip Newmark and colleagues describe conserved germ
cell-intrinsicfactorsandsomaticallyderivedsignalsthatcoordinategermcell
Preface xiii
development in the sexual strains. During regeneration, the “germ cell
cycle” is broken and dividing neoblast not only regenerates every part of
the body but also generates germ cells “de novo.” Thus, similar to the
emerging findings in mouse and human cultures, the distinction between
pluripotency and germ cells may be more plastic than previously thought.
Of all primordial germ cells in the body only a tiny fraction will ever
contributetoagermlinestemcellorsuitableeggorspermforreproduction.
In Chapter 5, Diana Laird and colleagues explore how heterogeneity and
selection during different stages of the germline life cycles may influence
thesuccessofgermcellsandultimatelybenefitnextgenerations.Selection,
regeneration, and homeostasis are of central importance during spermato-
genesis. In Chapters 6 and 7, some of the best-understood germline stem
cellsystemsarediscussed:theDrosophilaandmousetestes.Progressinboth
systems has been made by linking genetic and molecular analysis with
unprecedented advances in life imaging. These two systems exhibit mech-
anisms that maintain homeostasis between stem cells renewal and differen-
tiating population, that replenish germ line stem cells upon aging or injury
andthat‘reset’theclockforrejuvenationduringsuccessivegeneration,such
as telomere lengthening and rDNA repair that may account for rejuvena-
tion.Butthesesystemshavestrikinglydifferentmorphologies.Theflystem
cell niche is a morphologically highly ordered system of germ cells and
somatic support cells. At the tip of the testis (or ovary in flies) designated
germline stem cells divide predominantly asymmetrically, under the
control of signals from the somatic niche, to produce a new stem cell and
adifferentiatingcell,whichwillgoontoproducesperm(oreggs).However,
as Yukiko Yamashita and colleagues (Chapter 6) describe, germ cell
populations are germ cell populations are more plastic than previously
thought and stem cells can be rejuvenated by dedifferentiation of already
partially differentiated germ cells. Shosei Yoshida (Chapter 7) provides an
in-depth look of spermiogenesis in the mouse that questions and expands
someoftheestablishedviewsofthissystem.Incontrasttothefly,theniche
system in mouse is made up of a spatially open microenvironment, where
sperm stem cells are motile and part of a flexible system of undifferentiated
spermatogonia. These gradually commit toward differentiation possibly
guided by their susceptibility for signals from the somatic microenviron-
ment. With millions of sperm produced only one is needed to fertilize an
egg. Mariana Wolfner and her colleagues discussin Chapter 8 mechanisms
of “sperm success” and the interdependence between female and male
reproductive biology. In addition, the immune system plays an important
xiv Preface
role in reproduction. While needed to maintain a healthy body, its inert
defensemechanismsagainstintruderscanhaveantagonisticeffectsonsperm
success that need to be overcome for successful reproduction.
In conclusion, I have tremendously enjoyed reading these exciting
chapters and want to thank the authors not only for their scholarly work
but also their courage to be provocative and speculative. With no doubt,
enormous progress has been made in understanding germ cell biology.
Yet,atthesametime,itishumblingtorealizethatwestilllackafirmgrasp
of understanding even the first principles that underlie immortality. I am
indebtedtoPaulWassarman,whotwistedmyarmtoundergothisendeavor,
toShellieBryant,whostoodbymeduringthepreparationofthisbookand
to Kristen Dancel-Manning, who created the cover illustration. Finally, a
big ‘thank you’ to my lab members, past and present, who share my love
of everything germline.
RUTH LEHMANN
HHMI and Kimmel Center for Biology and
Medicine of the Skirball Institute, Department of Cell Biology,
New York University School of Medicine,
New York, NY, United States
CHAPTER ONE
The vertebrate Balbiani body,
germ plasm, and oocyte polarity
Allison Jamieson-Lucy, Mary C. Mullins*
DepartmentofCellandDevelopmentalBiology,UniversityofPennsylvaniaPerelmanSchoolofMedicine,
Philadelphia,PA,UnitedStates
*Correspondingauthor:e-mailaddress:[email protected]
Contents
1. Introduction 2
2. Inductiveandinheritedgermcellspecification 3
3. Inheritanceofgermplasm 6
4. TheBalbianibody:Aconservedoocyteorganelle 8
5. EarlyoocytedevelopmentandtheBalbianibodyinmice 11
6. Earlyoocytedevelopmentinzebrafish 13
7. TheBalbianibodyinzebrafishandfrogs 15
8. TheroleofmitochondriaintheBalbianibody 17
9. Buckyball:AnessentialBalbianibodyprotein 19
10. Macf1andBalbianibodydisassembly 21
11. SecondarypathwaymRNAlocalization 23
12. AnimalpolemRNAlocalization 23
13. Concludingremarks 24
Acknowledgments 25
References 25
Abstract
The fate of future generations depends on a high-quality germ line. For a female to
successfullyproduceoffspring,heroocytesmustbesuccessfullyspecifiedandtheircon-
tents meticulously organized. Germ cells are specified by two general mechanisms:
inductive and inherited. In the inductive mechanism, the primordial germ cells
(PGCs)areinducedbysignalsfromthesurroundingcells.Intheinheritedmechanism,
PGCsare specified bypassing localizedgerm plasm materialfrom theoocyte to the
futuregermcells.TheBalbianibody,aconservedoocyteaggregate,facilitatestheorga-
nizationoftheoocyteintoapolarizedcellwithdiscretecytoplasmicdomains,including
localizingthegermplasm.Inthemouse,theBalbianibodyisimplicatedinoocytesur-
vival,whileinfrogsandzebrafishtheBalbianibodycarriesspecificmRNAstothevegetal
pole. These asymmetric mRNAs form the foundation of the functionally polarized
oocyte and play important roles in axial patterning and germ plasm formation of
theembryo.
CurrentTopicsinDevelopmentalBiology,Volume135 #2019ElsevierInc. 1
ISSN0070-2153 Allrightsreserved.
https://doi.org/10.1016/bs.ctdb.2019.04.003