Download Development of skeleton

Development of the Skeletal System
 Principles
& Mechanisms
 Histogenesis
 Cartilage
 Bone
Intramembranous bone formation
Intracartilaginous (Endochondrial) bone formation
 Development of the skeleton
 Axial skeleton
 Appendicular skeleton
1
Skeletal development: Paraxial mesoderm
2
Skeletal development: Somite formation
3
Formation of
sclerotome
 Sclerotome:
ventromedial part
 Dermatomyotome:
dorsolateral part
4
Formation of
myotome and
dermatome
 Dermatomyotome:
 Myotome:
form
myoblast (muscle
primodium)
 Dermatome: form
dermis of skin
5
Development of skeleton: Overview
mesoderm → Somite →
 Sclerotome
 Dermatomyotome → Dermatome, Myotome
 Mesenchyme: loosely organized embryonic connective
tissue to form fibroblasts, chondroblasts, osteoblasts
 Source
Mesodermal cells: limbs & trunks
Neural crest cell: migrating into pharyngeal arches
to form craniofacial structures
 Paraxial
6
Principles of skeletal development
 Types
of skeleton
 Axial skeleton
Vertebral column
Skull
 Appendicular skeleton
Limb bones
 Sequence
 Mesenchymal stage
 Cartilagenous stage
 Bone stage
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Development of Vertebrae
4-week embryo
8
Development of vertebrae
 Formation
of vertebrae
 at 4th week
 differential growth of sclerotomal cells
 Vertebrae
 Body: centrum (notochord)
 Arch: mesenchyme surrounding neural tube
 Costal process/Rib: mesenschyme of body wall
 Influenced by Pax-1 gene
9
Mesenchymal stage of vertebral development
4-week embryo
10
Mesenchymal stage of vertebrae: 4-week
Condensation
of
sclerotomal cells
Around notochord,
Surrounding neural
tube
In body wall
Each sclerotome with
Cranial loose
mesenchyme
Caudal dense
mesenchyme
11
Mesenchymal stage of vertebrae: 5-week (1/2)
 Nucleus
pulposus:
expansion of
notochord
between vertebrae
 Annulus fibrous:
circular fibers
surrouding
nucleus pulposus
12
Mesenchymal stage of vertebrae: 5-week (2/2)
 Vertebral
body:
degeneration of notochord,
replaced by centrum
 Vertebral (neural) arch:
from mesencyme
surrounding neural tube
 Costal process (ribs in
throax): from mesenchyme
of body wall
13
Cartilaginous stage of vertebrae: 6-week
 Fusion
of 2 chondrification centers in centrum
 Fusion of 2 chondrification centers in vertebral arch with
centrum
 Spinous / transverse processes: extension of chondrification
centers in vertebral arch
14
Bone stage of vertebrae: ossification centers
3
primary ossification centers at 7-8 week
 One in centrum; One in each half of vertebral arch
 5 secondary ossification centers at puberty
 One for tip of spinous process
 One for tip of each transverse process
 Two in annular epiphyses
15
Vertebrae after birth
 Fusion
of vertebral arches:
at 3-5 years old; begin in
lumbar region, progress
cranially
 Neurocentral joint: between
vertebral arch and centrum;
permit growth of vertebral
archs; disappear at 3-6
years old
16
Pax-1



DNA-binding transcriptional
activator
Highly expressed in developing
sclerotome, pharyngeal pouches,
facial mesenchymes
Mouse phenotypes with
deformed vertebrate: undulated
17
Pax-1 in spine development: undulated
18
Development of skull
 Skull
 Neurocranium:
protection for brain
 Viscerocranium: skeleton of face
 Sequence
 Mesenchyma
 Cartilaginous cranium
 Membranous cranium: intramembranous bone formation
 Postnatal growth
19
Development of Neurocranium
 Cartilaginous
neurocranium = Chondrocranium
 Initially by fusion of cartilages; Later by
endochondral ossification to form base of skull
 Sequence of ossification pattern:
occipital bone
basisphenoid bone (body of sphenoid bone)
ethmoid bone
 Membranous neurocranium
 intramembranous ossification
20
Cartilaginous neurocranium
 Parachordal
cartilage:
from cranial end of
notochord, fuse with
cartilages from
sclerotome of occipital
somite
 form base of occipital
bone
 form foramen magnum
by extensive growth
around spinal cords
Nasal capsules
21
Cartilaginous neurocranium
 Trabeculae
cranii: fuse to
form body of ethmoid
bone
 Nasal capsules: around
nasal sac, form ethmoid
bone
 Hypophyseal cartilage:
around pituitary gland
(hypophysis cerebri); fuse
to form body of sphenoid
bone
22
Cartilaginous neurocranium: 12-week
 Ala
orbitalis: form lesser
wing of sphenoid
 Ala temporalis: form
greater wing of
sphenoid
 Otic capsules: form
petrous and mastoid
parts of temporal bone
23
Membranous neurocranium
 Calvaria:
intramembranous ossification
 Fontanelles: between sutures
24
Postnatal changes in skull (calvaria)
 Major
changes
 Disappearance of fontanelles / suture
 Growth of bone by itself to adapt the brain growth
 Closure of fontanelles
 Anterolateral (sphenoid) fontanelles: 2-3 months after
birth; suture sremain for several years
 Posterior fontanelles: by 1 year of age
 Anterior fontanelle: by 2 year of age
25
Cartilaginous viscerocranium: 1st, 2nd pharyngeal arches
 1st
arch cartilage
(Meckel cartilage):
incus, malleus
 2nd arch cartilage
(Reichert cartilage)
 Dorsal end: stapes,
styloid process of
temporal bone
 Ventral end: lesser
cornu/superior
part of hyoid bone
26
Cartilaginous viscerocranium: 3rd & 4th arches
 3rd
arch cartilage:
greater corn/inferior
part of hyoid bone
 4th/6th arch
cartilages:
laryngeal cartilages
except epiglottis
27
Membranous viscerocranium
 Maxillary
prominence
of 1st pharyngeal arch:
squamous temporal,
maxillary, zygomatic
bones
 Mandibular
prominence of 1st
pharyngeal arch:
condense around
Meckel cartilage to
become mandible
28
Development of long bones
33 days
28 days
5th
week
6th week
29
Time table for the development of
appendicular skeleton
bone models: begin at 5th week
 Chondrofication to form hyaline cartilage bone models:
begin at 6th week
 Primary center of ossification: begin from 8th-12th week
 Secondary center of ossification: begin from 34th-38th
week
 Mesenchymal
30
Hox genes: the discovery of 4-wing fly
EB Lewis, C Nusslein-Volhard, EF Wieschaus
wild type
mutant 4-winged
31
HOX genes in mammals for body planning
32
Hox mutations in humans
 Syndactyly:
a rare dominant
malformation in distal limbs;
between 3rd and 4th fingers
 Mutation in HoxD13
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Summary of Neurocranium and Viscerovranium
 Mem. neuro: frontal,
parietal
 Cart. neuro: sphenoid,
occipital, temporal
(petrous, mastoid)
 Mem. viscero:
mandible, maxilla,
temporal (squama)
 Cart. viscero: auditory,
temporal (styloid),
hyoid, thyroid
34
Overview of Myotome
41-day embryo
41-day embryo


Myotome of a somite → ventral hypaxial, dorsal epaxial divisions
Spinal nerve →
 Ventral primary ramus for hypaxial division and limb muscles
 Dorsal primary ramus for epaxial division
35
Derivatives: Epaxial division of myotome
7-week embryo
 Extensor
o
6-week embryo
muscles of neck & vertebral column
But extensors of sacral & coccygeal myotomes → degenerate
→ dorsal sacrococcygeal ligaments
36
Derivatives: Hypaxial division of myotome
7-week embryo




8-week embryo
Cervical myotome: scalene, prevertebral, geniohyoid, infrahyoid m.
Thoracic myotome: lateral / ventral flexor muscles of vertebral column
Lumbar myotome: quadratus lumborum etc
Sacrococcygeal myotome: pelvic diaphgragm, striated m. of
anus/genital organs
37
Development of Facial / Tongue muscles
8-week embryo
41 days


Pharyngeal arch muscles: mastication, facial expression, pharynx,
larynx (innervated by pharyngeal arch nerves)
Tongue muscles: from 4 occipital (postotic) myotomes; indeed the first
eventually disappears; innervated by hypoglossal nerve
38
Derivatives of Extraocular muscles
8-week embryo
6-week
 Ocular
muscles: from mesenchymal cells near prechoral plate
→ preotic myotome → extraocular muscle (EOM)
39
Development of Limb muscles
Limb bud
6-week

Limb muscles: from myoblasts surrounding bones (somites)
 Precursor myogenic cells in ventral dermatomyotome (epithelium in
nature) → migrate to premodium of limbs after mesenchymeepithelium transformation
40
Myotome: Summary
of a somite →
 ventral hypaxial division
 dorsal epaxial division
 Spinal nerve →
 Ventral primary ramus for hypaxial division
 Dorsal primary ramus for epaxial division
 Intercostal muscles: remain segmented
 Most other muscles (limbs): non-segmented
because of myoblast migration
 Myotome
41
Development of Muscles: Summary
 Muscular
system: develop from mesoderm or derivatives
 Mesenchyme of myotome in somites or neural crestinduced pharyngeal arches (exception: iris from
neuroectoderm)
 Myoblasts
 Skeletal muscles
 Head/Neck: from mesenchyme of pharyngeal arches
 Trunk: from mesoderm in myotome of somite
 Limb: from myogenic precursor cells in limb buds
(originating from somites as well)
42
Pharyngeal arch: summary
Arch
Nerve
Muscles
Skeletal structures
First,
mandibular
Trigeminal (V3) mastication, tensor
tympani, veli
palatini
malleus, incus
Second,
hyoid
CN 7 (facial)
facial expression,
stapedius,
stylohyoid
stapes, styloid proc,
hyoid (upper,
lesser cornu)
Third
CN 9 (glossopharyngeal)
stylopharyngeaus
Hyoid (lower,
greater cornu)
Fourth /
Sixth
CN 10 (superior cricothyroid, levator
/ recurrent
veli palatini,
pharyngeal
laryngeal)
constrictor
Cartilage (thyroid,
cricoid, arytenoid,
corniculate,
cuneiform)
43
Molecular mechanisms of myogenesis
BMP-4




Inductive factors from
ectoderm and dorsal neural
tube: wnt, BMP-4
Inductive factor from
notochord and ventral neural
tube: Shh
Activation of Pax-3 and Myf-5
in dermatomyotome
Migratory activity: Pax3
44
Control of muscle size
 Myostatin
to TGF-β family,
important for growth and
differentiation
 expressed at myotome of
somites
 Mutation: causing muscle
hypertrophy
 belong
45
Myostatin mutation with muscle hypertrophy
46
Early stages of
limb development



Limb buds: 4th week, small
elevation in ventrolateral
body wall
Upper limb bud: 26-27
days; caudal cervical
segments
Lower limb bud: 28-30
days; lumbar/upper sacral
segments
47
Development of
limb buds
 Limb
bud: a mass of
mesenchyme with
covering ectoderm
 Apical ectodermal ridge
(AER): thinning of
ectoderm at apex of
each limb bud; a multilayered epithelium
48
Formation of hands and feet (4th-8th week)
U: 27 days
L: 28 days




32 days
36 days
41 days
46 days
46 days
49 days
50 days
52 days
52 days
56 days
Plate: hand plate (by 6th wk), foot plate (7th wk)
Digital rays by condensation of mesenchyme; Mesenchymal premodia
of bone (phalanges)
Notches between digital rays: breakdown of intervening loose
mesenchyme; Mechanism: programmed cell death (apoptosis) by BMP
 Clinical correlation: syndactyly by blocking apoptosis and BMP
Separate digits: by 8th wk
49
Anomalies of limbs
 Critical
period for limb formation
 24-36 days post-fertilization
(thalidomide)
 Exposure before day 33:
absence/hypoplasia of thumbs
 Thalidomide: as sedative/antinausea agent (withdrawn
in1961); contraindicated in
women of childbearing age
50
Limb anomalies: thalidomide
51
Story of Frances Oldham Kelsey, MD, PhD



“In 1960, Kelsey was hired by the FDA in
Washington, DC. At that time, she "was one of only
seven full-time and four young part-time physicians
reviewing drugs" for the FDA. One of her first
assignments at the FDA, was to review application
by Richardson Merrell for the drug thalidomide
(under the tradename Kevadon).
Even though it had already been approved in over
20 European and African countries, she withheld
approval for the drug, and requested further studies.
Despite pressure from thalidomide's manufacturer,
Kelsey persisted in requesting additional information
to explain an English study which documented a
nervous system side effect.”
http://en.wikipedia.org/wiki/Frances_Oldham_Kelsey
52
Summary of Limb development
at the end of 4th week
 Slight elevation of ventrolateral body wall (upper limbs:
2 days earlier than lower limbs)
 Limb buds: from mesoderm & ectoderm
 Apical ectodermal ridge (AER):
 Inductive influence on limb mesenchyme
 promoting growth & development of limbs
 Elongation: proliferation of mesenchyme
 Formation of digits: with involvement of programmed cell
death
 Begin
53