Human Engineering Cloning, Stem-Cell Research, and In Vitro Fertilization.
Human Development: Fertilization through gastrulation
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Transcript of Human Development: Fertilization through gastrulation
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Human Development:Fertilization through gastrulation
Michael M. Shen, Ph.D.
Departments of Medicine and Genetics & DevelopmentColumbia University Medical Center
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Gastrulation movements in the frog embryo
Vegetal view
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From blastula to gastrula
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The first week of development
• Fertilization
• Cleavage stages
• Blastocyst formation
• Early lineage specification
• Implantation
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The second week of development
• Trophoblast differentiation
• Yolk sac formation
• Anterior-posterior axis patterning
• Initiation of gastrulation
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The third week of development
• Endoderm and mesoderm ingression
• Mesoderm lineage specification
• Left-right patterning
• Neural plate formation
• Axial midline formation
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Reductive cleavage
Blastomere potency
Inside-outside allocation of lineage
progenitors
Compaction
Blastocyst formation
Emerging morphological asymmetry
Pre-implantation mouse development
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Human embryo development in culture
Fertilization
CleavagesCompactio
n
Blastocyst formation
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Early cleavages of the mouse embryo
(Bischoff et al. (2008))
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Key properties of vertebrate embryogenesis
Regulative development
Early blastomeres are totipotent
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Regulative development of the vertebrate embryo
(DeRobertis (2006))
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Zygotic genome activity
Mid-preimplantation genome activity
(Wang and Dey (2006))
Gene expression at pre-implantation stages in the mouse
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Cell types of the blastocyst
Primitive ectoderm(epiblast) Trophectoderm
Primitive endoderm
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(Wang and Dey (2006))
Specification of early lineages
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Model for primitive endoderm (hypoblast) specification
(Chazaud et al. (2006))
Inner cell mass
TrophectodermNanog expression
Gata6 expression
Epiblast
Primitiveendoderm
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Can contribute to all embryonic cell types in chimeras – including the germ line
Pluripotency of mouse ES cells
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Early lineages and stem cells in the mouse embryo
TS cells
ES cells
XEN cells
EpiSC cells
Mouse EpiSC cells resemble human ES cells
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Process of implantation
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Formation of extraembryonic tissues
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Key properties of vertebrate embryogenesis
Regulative development
Patterning at a distance by soluble morphogens
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Two major signaling pathways regulate early patterning and
differentation
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Schematic pathway for canonical Wnt/
beta-catenin signaling
Wnt ligand absentWnt ligand present
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Schematic pathway for TGF-beta signaling
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The Nodal signaling pathway
(Cripto, Cryptic)
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Key properties of vertebrate embryogenesis
Regulative development
Patterning at a distance by soluble morphogens
Common patterning mechanisms underlie distinct embryo morphologies
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Schematic of early mouse development
(Adapted from Hogan et al. (1994))
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(Eakin and Behringer)
Extraembryonic
ectoderm
Mesoderm
Extraembryonic
endoderm
Definitive endoder
m
Ectoderm
mouse
humanCup-shaped vs discoid
Morphological relationship between mouse and human
embryos
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Key properties of vertebrate embryogenesis
Regulative development
Patterning at a distance by soluble morphogens
Common patterning mechanisms underlie distinct embryo morphologies
Antagonism of secreted ligands and inhibitors
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Specification of the anterior-posterior axis in the mouse
Nodal and Cripto activity Nodal inhibitor activity (Lefty, Cerberus)
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Movement of the anterior visceral endoderm
View from anterior side
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Relationship of blastodisc to implantation site
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Formation of the primitive streak
Expression of Brachyury in chick embryo
Node
Streak
Anterior
Posterior
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Early embryogenesis in the chick
Anterior
Posterior
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Ingression of nascent endoderm and mesoderm through the
streak• Delamination of
epiblast cells
• Movement through the streak
• Initial ingression of endoderm
• Subsequent ingression of mesoderm
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Anterior and lateral migration of mesoderm
• Anterior migration of mesoderm:
• Axial (prechordal)
• Cardiac
• Lateral distance from midline determines mesoderm type:
• Axial (e.g., notochord)
• Paraxial (somites)
• Intermediate (e.g., kidney)
• Lateral (e.g, limbs)
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Regional differentiation of mesoderm
AxialParaxial
IntermediateSomatic
Splanchnic
Chick embryo
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Anterior-posterior patterning of axial mesoderm
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Key properties of vertebrate embryogenesis
Regulative development
Patterning at a distance by soluble morphogens
Common patterning mechanisms underlie distinct embryo morphologies
Antagonism of secreted ligands and inhibitors
Instructive inductive interactions
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Spemann-Mangold organizer experiment
Blastopore lip transplantation
(DeRobertis and Kuroda (2004))
Induction of secondary axis
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Injection of Wnts or Nodal can induce a secondary axis
• Injection of mRNA into dorsal marginal zone
• Wnt8 (complete axis)
• Nodal (partial axis)
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Formation of the neural plate
Macaque embryo(similar to 20 day human embryo)
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AVE Anterior visceral endodermEPI Epiblast
NE Neural progenitorEGO Early gastrula organizer
PS Primitive streak
Inductive interactions and head formation
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Dorsoventral patterning by axial and paraxial mesoderm
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Holoprosencephaly in Cripto hypomorphs
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Defective forebrain patterning and axial mesoderm formation
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Spectrum of human holoprosencephaly
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(Kosaki and Casey (1998))
Complex L-R laterality of tissues
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Nomenclature for L-R laterality phenotypes
(Capdevila et al. (2000))
Situs solitus: normal organ position
Situs inversus: complete reversal of organ position
Isomerism: mirror image duplication of tissue morphology
Heterotaxia: discordant and randomized organ position
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Initial symmetry breaking
Stages of L-R laterality determination
Nodal flow model
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Initial symmetry breaking
Propagation and maintenance of an asymmetric signal
Specification of tissue-specific laterality
Stages of L-R laterality determination
Asymmetric gene expression
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Nodal
Lefty
(Beddington and Robertson (1998))
Asymmetric expression of Nodal and Lefty
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Left-right laterality defects in Cryptic mutants
Wild-type
Wild-type Cryptic–/–
Cryptic–/–
Cryptic–/–
Wild-type Cryptic–/–
Wild-typeCryptic–/–
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Cardiac defects in Cryptic mutants
Wild-type Cryptic–/– Cryptic–/–
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Transposition of the great arteries
Normal Transposed
Wild-type Cryptic–/–
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Morphological changes at early post-gastrulation stages
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