Lecture Section IV Outline
Paraxial and Intermediate Mesoderm
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Vocabulary:
o Sclerotome: Forms vertebral and rib cartilage
o Myotome: Formsmuscles of back, rib cage, and abdomen
o Dermamyotome: Forms dermal cells, limb muscle
o Syndetome: Formsmost dorsal tendons
o Arthrotome: Formsmost central, vertebral joints/discs, proximal ribs
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The mesoderm forms at the same time as the ectoderm (during gastrulation
and neurulation)
o Paraxial mesoderm(head mesoderm and somites)
 Forms structures surrounding the spinal cord: somites and the
cartilage derived from them, bone, muscle and dermis.
o Intermediate mesoderm
 Forms the kidneys, gonads, ductwork and the adrenal cortex.
o Lateral plate mesoderm and chordamesoderm also form
Paraxial Mesoderm
1. Establishment of periodicity
a. Periodic somite formation inherent to mesoderm
b. Two waves of secreted activity
i. FGF from anterior to posterior
ii. ??? from posterior to anterior (evidenced by Hairy1
expression)
c. FGF and ??? cause delta and notch to form on adjacent cells
d. Delta-notch interaction causes Hairy1 expression to remain on
e. Where Hairy1 remains on, somite separation occurs
2. Fissure formation (separation)
a. Hairy1 expression causes ephrin expression
b. Ephrin causes repulsion of anterior part of presomitic mesoderm
3. Epithelialization
a. Paraxial mesoderm up until this point is just a mass of closely
associated mesenchymal cells
b. Cells respond to hairy1 by expressing n-cadherins
i. Causes MTE
c. Epithelial sheet begins to form on posterior edge
4. Specification
a. Specification occurs according to the position along the anteriorposterior line due to proximity to Hox genes
5. Differentiation
a. Somites are competent to form all derivative cell types
b. Surrounding structures determines fate
i. First step is the induction of the sclerotome formation by the
notochord
1. ETM migration of cells from the sclerotome surrounds
the vertebrae and later forms cartilage, leaving behind
the dermamyotome.
ii. Next step is segregation of dermamyotome
1. Emergence of dermatome, primaxial and abaxial
dermamyotome
a. Dermatome: forms back dermis and brown fat
b. Primaxial myotome: forms back and intercostal
muscles
c. Abaxial myotome: forms abdominal muscle,
tongue, limbs
2. Myotome proliferation
a. Becomes the stem cell population (or committed
progenitors) that supports all muscles growth.
The bulk of muscle cells come from these cells
b. Divides like crazy. Primaxial and abaxial cells get
the muscle started. Myotome finishes the job.
c. Present for the duration of the organism’s life.
6. Tissue formation
a. Myogenesis: Muscle Formation
i. Muscles form from the somitic mesoderm
1. Cells from the center of the somite (myotome) exit the
cell cycle when an injury to the muscle occurs and
differentiates to support.
a. Paracrine signals from the neural tube/
notochord induce somitic cells to express MyoD
(not until injury) and Myf-5. These are TFs for
muscle genes and for the proteins themselves.
i. Wnt and Shh
b. Myotome cells begin dividing and are now called
myoblasts
i. FGF
c. These myoblasts line up end-to-end and fuse to
form multinucleated cells (myotubes).
i. Fibronectin, integrins, cadherins/CAM,
myogenin.
d. Myotubes begin to fuse and mature (fusion with
myoblasts [stem cells])
i. Meltrin, interleukin-4
ii. Interestingly, tubes from different species
will fuse – no discrimination.
e. The mature muscle fiber is now able to begin
contracting.
b. Osteogenesis: Bone Formation
i. Four different sources of cells and two different processes
1. Endochondrial ossification
a. Somites form axial skeleton
b. Lateral plate mesoderm form limb skeleton
2. Intramembranous ossification
a. Cranial NC forms bones of the face and head
b. Mesodermal mesenchyme forms the patella and
periosteum
ii. Endochondrial Ossification Mechanism
1. Shh from the notochord causes cells from the
sclerotome to undergo an ETM transition and migrate.
a. These cells are now committed chondrocytes
2. When they get to where they are going they form
compact nodules in the model of the bone they will
form.
3. They then begin proliferating
4. Along the middle, the cells undergo differentiation and
grow very large, secreting calcium into their ECM,
killing themselves.
5. Calcified, dead chondrocytes receive an Ihh signal and
differentiate into osteoblasts.
6. This spreads in both directions.
a. Fronts of chondrocytes leading cell death are
known as growth plates
b. This expansion occurs through puberty
7. As chondrocytes die, signal is sent to supply blood to
osteoclasts and osteoblasts
iii. Endochondrial Ossification of Vertebrae
1. Sclerotome mesenchymeare attractedby notochordand
neural tubesecretions
2. As motor axonsextend towardmuscles, they gothrough
sclerotomeportion of the somite and split themrostralto-caudal and connect to muscle on the other side.
3. The caudal end of one thenrecombines with the
rostralend of the next to form thebone model and then
bone.
c. Vascular Replacement in the Dorsal Aorta
i. Sclerotome cells migrate to dorsal aorta and replace
endothelial and smooth muscle cells
1. Reason why unclear
d. The Syndetome: Tendon Formation
i. Last layer of cells before sclerotome undergoes ETM transition
and leaves the somite; muscle progenitor cells stimulate the
syndetome to become tendon instead of cartilage or muscle.
1. Serves as a connection between muscles and bones
Intermediate Mesoderm
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Adult kidney very complex
Embryo has an increasing need to filter blood
o Intermediate mesoderm forms pronephric (Wolffian) duct, which
serves as the organizer.
 Duct induces three stages of kidney
 First two transitory, the third persist
 Pronephros
o Pronephric duct forms as part of pronephros
 Only functional in water-dwelling
organisms
 Mesonephros
o Functional in humans and most other organisms
 Heart beings beating early creating a need
for filtration
o Further induction occurs from Wolffian Duct and
gonadal structure forms
o Metanephrosbegins to form
 Metanephros
o Will end up being adult kidney
o Formed through reciprocal induction between
Wolffian Duct and intermediate mesoderm
(mesenchymal)
 Bud from duct recruits mesenchyme
(soluble signals) to condense around it
 Mesenchymal cells signal back to bud,
telling it to become more complex
 Further mesenchymal recruitment
 Capped with glomerulus
Lateral Mesoderm and Endoderm
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Vocabulary:
o Somatopleure: somatic mesoderm plus ectoderm
o Splanchnopleure: splanchnic mesoderm plus endoderm
o Coelom: body cavity forms between them
Coelom
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Two cavities exists which eventually fuse
Runs from neck to anus in vertebrates
Portioned off by folds of somatic mesoderm
o Pleural cavity: surrounds the thorax and lungs
o Pericardial cavity: surrounds the heart
o Peritoneal cavity: surrounds the abdominal organs
Heart Development
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First functional organ
o Must switch from diffusion of nutrients to active transport early in
development to facilitate growth
Three stages of development
o Tube formation
 Specified heart cells start out as heart field in epiblast
 Migrate through at primitive groove as mesenchyme–
condenses into splanchnic mesoderm using cadherins and
association with endoderm
 Outflow guys migrate first and forward
 Inflow second
 Two endocardial tubes form on either side of the midline
 MET of endocardial cells to migrate in between the
mesoderm and endoderm
o Cardiogenic mesoderm migrations from lateral
plate mesoderm
 At the same time endoderm is folding inward and
continues to do so until it forms its own tube, enclosing
the two heart tubes (endocardial primordia
[surrounded by myocardial progenitors])
o Fuse into one tube
 Signals to surrounding mesoderm to
differentiate into myocardium
 Tube terminates at a fork on each end because of this fusion
 Can form multiple arteries and veins this way
o Inflow tract – Veins
 Vitelline veins
o Outflow tract – Arteries
 Pulmonary
 Systemic
o Looping
 Inflow track loops up to form atria on top of ventricles
 Driven by more cell division on one side (left) than the other
Nodal and Pitx2 determine right vs. left looping and LR
asymmetry
o Chamber formation
 Septa separate two atria and two ventricles (grow toward
cushion)
 Valve formation – from myocardium
 Keep blood from flowing back into chambers it just left
 The truncus arteriosis becomes septated allowing flow from
right ventricle to lungsand the other from left ventricle to the
body
Embryonic circulatory system
o Foramen ovale shunts blood from RA to LA
 Blood must circulate outside of embryo to become oxygenated
Redirection of blood flow at birth
o Ductus arteriosus (shunts blood from PV to aorta) undergoes
apoptosis
o Forman ovale grows closed – signaled by pressure
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Blood Vessel Development
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Form independently of the heart
Needs to form early to connect with extraembryonic membrane
o Extraembryonic membrane fulfills needs of embryo before supporting
structures have been developed
 GI tract
 Lungs
 Kidneys
Evolution
o Mammals still extend vessels to empty yolk sac
o Birds and mammals build six aortic arches as if we had gills
Fluid dynamics
o Organized size variance controls volume
o Branching controls speed
Vasculogenesis
o De novo differentiation of mesoderm into endothelium
o Recruits smooth muscle
Angiogenesis
o Starts from intact blood vessel
 Growth and remodeling in response to blood flow and
recruitment signals
Blood Cell Formation
o Starts in extraembryonic mesoderm and in large embryonic blood
vessels
o Blood islands
 Primitive blood cells form
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Lymphatic Vessels
o Form from jugular vein
o Sprouts as lymphatic sacs by angiogenesis
o Continues to form secondary drainage system
o Major conduit for immune cells
Hematopoietic SC
o Come from splanchnic mesoderm
Development of the Endoderm
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Digestive tube
o Anterior endoderm forms anterior intestinal portal
o Posterior endoderm forms posterior intestinal portal
o Midgut goes through expansion and contraction to yolk
o Each end has ectodermal cap, then forms an entrance
Derivatives
o Head and neck structures
 Cranial NC migrate through this endoderm, contributing to the
surrounding structures
o Gut tube forms esophagus, stomach, SI, LI, rectum
o Gut tube buds out to form liver, gall bladder, pancreas
 Localized Wnt/B-Catenin and retinoic acid cause budding
Anterior-Posterior Specification
o Hox, cSox2, Pdx1, cdxC, cdxA
o Reciprocal induction between endoderm and mesoderm
 Heart induced liver
 Liver induced epicardium
 Pancreas
Extraembyronic Membranes
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Adaptations for development on dry land
Four sets of extraembryonic membranes
o Somatopleure forms amnion and chorion
 Amnion: covers embryo to keep it from drying out
 Chorion: surrounds embryo and control gas exchange
o Splanchnopleure forms yolk sac and allantois
 Yolk sac: surrounds yolk
 Allantois: space for waste
Limb Development
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Similarities
o Symmetry in all four limbs
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Architectural symmetry
 Extends to muscles, tendons, cartilage, vessels, nerves
Size
Growth and development
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Differences
o Rostral-Caudal asymmetry
o Left-Right asymmetry
 Mirror image
o Structural polarity
 Proximal-Distal, Anterior-Posterior, Dorsal-Ventral
Hox Genes
o Combination of how genes influences what limb structures will form
 Deletion of genes leads to deletion of structure
“Morphogenetic Rules”
o Grafting limb buds from one organism can induce limbs in different
species
Limb Field -> Limb Bud Formation
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Limb Field
o Occurs in mesoderm
 Anterior to posterior
o Forms in a ring – surrounded by cells that will not contribute to limb
unless other cells are damaged
 Peribrachial flank tissue
 Free limb
 Shoulder girdle
Limb Bud
o Begins as a bulge in ectoderm
 Bulge due to migrations of the somatic mesoderm (bone) and
abaxial myotome (muscle)
 Pronephron seems to cause EMT
Proximal-Distal Patterning
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FGF10 from mesodermal mesenchyme in the sub-ectodermal space signals to
overlying ectoderm to form apical ridge (AER)
AER communicates back to the mesoderm, influencing development there
o Hox genes
o Called progress zone (PZ)
Anterior-Posterior Patterning
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Zone of Polarizing Activity
o Piece of mesoderm at the junction of the young limb bud and the body
wall
o When a ZPA is grafted to anterior limb bud mesoderm,
o Duplicated digits emerge as a mirror image of the normal digits
o Source of soluble signals (Shh)
 Forms anterior-posterior gradient
o Time of expression also factors into patterning
o BMP secretions in response to how much Shh and when you saw it
Dorsal-Ventral Patterning
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Determined by overlying ectoderm and Wnt7a (mostly)