Term 2 MSK wk 2 Flashcards
week 4 - 8 , limb development
Summarise 1st week of development [check with ToB]
- fertilisation
- zygot divides
- morula
- early blastocyst
- late blastocyst (trophoblast formation)
- implantation begins (inner cell mass formation )
summarise 2nd week of development [check with ToB]
- bilaminar embryonic disc formation
- lacunae appear in synctiotrophoblast, primary umbilical vesicle
- closing plug
- embryonic disc
summarise 3rd week of development
- primitive streak
- migration of mesenchymal cells
- trilaminar embryo
- neural plate and neural groove
Gastrulation = process by which ?
bi-laminar embryonic disc is converted into a tri-laminar embryonic disc containing 3 germ layers (ectoderm, endoderm, mesoderm)
What is gastrulation the beginning of ?
morphogenesis
what is morphogenesis ?
development of the form and structure of various organs and parts of the body
During gastrulation how is the mesoderm formed ?
specific regions of the epiblast migrate through different parts of the node and primitive streak
Which cells will form the notochord ?
cells migrating at the central and most cranial part of the node (axial mesoderm)
Epiblast cells migrating laterally form what ?
- paraxial mesoderm
- intermediate mesoderm
- lateral plate mesoderm
During 3rd week what does the paraxial mesoderm start to do ?
organise into segments = somitomeres
towards the end of the 3rd week what happens to the paraxial mesoderm ?
somitomeres further organise into somites, on each side of the neural tube
In what sequence do new somites appear in ?
cranio-caudal
New somites appear in cranio-caudal sequence at a rate of app. ….1… pairs/ day , until at the end of the ..2… weeks …3… pairs are present
- 3
- 5th
- 42-44
What do somites differentiate into ?
- sclerotome -> axial skeleton
- dermomyotome -> dermatome -> dermis and conncective tissue of back
- dermomyotome -> myotome -> axial and appendicular skeletal muscle
Region of derivative dermatome on somite
dorso-lateral
Region of derivative myotome on somite
ventral
Region of derivative sclerotome on somite
ventro-medial
How does axial and appendicular skeletal muscle form from somites ?
somites -> dermomyotome -> myotome -> myogenic cells -> myoblast -> axial and appendicular skeletal muscle
How does axial skeleton form from somites ?
somites -> sclerotome -> chondrocytes -> tendons & (cartilage -> ossification into bone -> axial skeleton)
Sclerotome is the ventro-medial region that contains cells that will give rise to what ?
cartilage cells (chondrocytes)
What is the dermamyotome ?
double layered structure that consists of dermatome + myotome
Although somites are transient structures they are an ……?
essential part of the developing body plan of the vertebrates
what are somites the building blocks for ?
the vertebrate body plan
what are somites essential for ?
- segmentation
- bone and musculature development
- creating template for nervous system
Although all somites look idnetical what will they form ?
different structures at different positions along the anterior-posterior axis
Ribs are derived only from somites forming the …… vertebrae ?
thoracic
What do distinct regions of each somite become ?
specific tissue and cell types as the body develops
What do somites determine ?
migration pattern of neural crest cells & spinal nerve axons
What forms the vertebrae?
resegmentation of the sclerotomes
What segments does each sclerotome split into ?
cranial and caudal
sclerotome splits into …1…. segments
as the segmental …2… nerves grow toward the cranial portion of the somite to innervate the …3….
the cranial segment of each sclerotome …4… with the caudal segment of the next cranial sclerotome to form a ..5…
- cranial and caudal
- spinal
- myotomes
- recombines
- vertebra
what does each myotome and dermatome retain ?
its innervation from its segment of origin
motor and sensory nerves innervate the body wall and limbs in a pattern that is based on what ?
segmental organization established by the somites
Developmental definition of dermatome
part of somite that gives rise to dermis
Developmental definition of myotome
gives rise to muscles
clinical definition of dermatome
an area of skin in which sensory nerves derive from a single spinal root
clinical definition of myotome
muscle/group of muscles supplied by a single spinal nerve
what levels are dermatomes divided into ?
- cervical
- thoracic
- lumbar
- sacral
- coccygeal
how many dermatomes in total ?
30
Testing of dermatomes is part of neurological examination looking for what ?
radiculopathy as sensation changes within a specific dermatome which may help in determining the pathological disc level
2 pathologies associated with dermatomes
- radiculopathies - commonly due to disc herniations from advanced age or trauma
- shingles - reactivation of varicella zoster virus
During the 5th week what happens to the peripheral nerves ?
they grow from the developing limb plexuses into the mesenchyme of the limb buds
How are the spinal nerve distributed during the 5th week suppling what ?
- distributed in segmental bands
- suppling both the dorsal and the ventral surfaces of the limb buds
Although the original dermatomal pattern changes during growth of the limbs what can be seen in the adult ?
an orderly sequence of distribution can still be recognised
When limbs extend and rotate what do they carry with them ?
their nerves
Limb skeleton develops how from the mesoderm ?
lateral plate mesoderm -> somatic (parietal) mesoderm -> limb skeleton
limb musculature develops how from the mesoderm?
paraxial mesoderm -> somites -> myotome -> limb musculature
connective tissue of the dermis develops how from the mesoderm ?
paraxial mesoderm -> somites -> dermatome -> connective tissue of the dermis
What does the lateral plate mesoderm divide into ?
- somatic (parietal) mesoderm
- limb skeleton
- bones of arm, forearm, hand, thigh, leg and foot
- blood vessels
- connective tissue (except of the dermis)
Antero-posterior axis refers to what ?
From 1st digit to 5th i.e. thumb to little finger
in Upper Limb
proximo-distal axis refers to what ?
Base of the limb to the tips of the digits
dorsal refers to what ?
Back of the hand & “top”of the foot
ventral refers to what ?
Palm of the hand & sole of the foot
Which weeks does limb morphogenesis take place ?
4th to 8th
what does limb development begin with ?
activation of a group of mesenchymal cells from the somatic (parietal) layer of lateral mesoderm that form limb buds
Upper limb buds:
1. develop on what day ?
2. develop as what at level of ?
3. upper thoracic segments =
- 24
- small bulges on lateral body wall at level of caudal cervial
- C5 to T1
lower limb buds:
1. develop when ?
2. form at what level ?
- by end of week 4
- lumbar and upper sacral segments (L1 to S1)
mesoderm of the early limb bud consists of …1.. cells supplied by a well-developed ..2.. network
- homogeneous mesenchymal
- vascular
Initially, the limb bud mesenchyme consists exclusively of cells derived from the ..1… mesoderm; these cells will give rise to the …2…
- lateral plate
- skeleton, connective tissue, and some blood vessels
Mesenchymal cells derived from the somites migrate into the limb bud as precursors of what ?
muscle and endothelial cells
cells from the neural crest will ultimately form what ?
- schwann cells of the nerves
- sensory nerves
- pigment cells (melanocytes)
Limb bud consist of a mesenchymal core derived from where ?
somatic (parietal) layer of lateral plate mesoderm
What is the limb bud that consists a mesenchymal core covered by ?
layer of cuboidal ectoderm
limb bud consisting of a mesenchumal core will form what of the limbs ?
the bones and conenctive tissues
How is the apical ectoderm ridge (AER) formed ?
ectoderm at the distal border of the limb thickens
What is the apical ectodermal ridge ?
a specialised multilayered epithelial structure
limb development occurs as the result of continuous interactions between what components of the limb bud ?
mesodermal and ectodermal
What does the apical ectodermal ridge induce in the limb bud ?
adjacent mesenchyme to remain as a population of undifferentiated, rapidly proliferating cells, the progress zone
Although the AER promotes outrgrowth , its own existence is reciprocally controlled by what ?
the mesoderm
- As the limb grows what happens to cells farther from the influence of the AER ?
- what happens in this manner ?
- they begin to differentiate into cartilage and muscle
- development of the limb proceeds proximodistally
List the important factors of the apical ectodermal ridge
1. critical for …
2. orchestrates …… in ….. direction (establishes …… axis of the limb)
3. marks the …. between ……. limb ectoderm - …… patterning
- limb bud outgrowth
- limb development, proximal to distal, proximo-distal
- boundary , dorsal and ventral , dorsoventral patterning
dorsoventral patterning is when ectoderm exterts …?
dorsalising and ventralising influences over mesenchyme core
When does the apical ectodermal ridge regress ?
after final stage of appearance of paddles
In 6 week old embryos what happens to the terminal portion of the limb buds ?
becomes flattened to form handplates + footplates
What happens to the mesenchymal tissue in the hand plates by the end of the 6th week of development ? when does this happen to foot plates ?
condense to form finger buds (digital rays) - which outline pattern of digits
week 7 - toe buds - digital rays
At the tip of each digital ray, a part of the AER does what ?
induces development of the mesenchyme into the mesenchymal primordia of the bones (phalanges) in the digits
intervening regions of mesenchyme undergo apoptosis forming what ? what happens by end of 8th week ?
notches between the digital rays and separate digits are produced by end of 8th week
what does the mesenchyme in a limb bud give rise to ?
bones, ligaments, and blood vessels
As the limb buds elongate what happens during the 5th week ?
- early part = mesenchymal models of bones formed by cellular aggregations
- later in week = chondrification centres appear
During the 6th week what happens to mesenchyme in the limb buds ?
- begin to condense and differentiate into chondrocytes
- mesenchymal bone models undergo chondrification to form hyaline cartilage bone models
What foreshadows the bodnes of the extremities ?
chondrification of mesenchymal bone models in the limbs to form hyaline cartilage bone models
By the end of the 6th week the entire limb skeleton is what ?
cartilaginous
In which week of development does osteogenesis of long bones begin ?
7th
Ossification centres are present in all long bone by the ….. week
12th
Osteogenesis of the long bones begins in the 7th week from ..1… in the …2.. (shaft) of the …3.. bones
- primary ossification centres
- diaphysis
- long
At birth what’s the difference between the ossificaiton of the diaphysis and epiphyses?
- diaphysis of bone is usually completely ossified
- 2 ends , epiphyses, are still cartilaginous
What plays an important role in growth in the length of the bones ?
epiphyseal plate
What the difference between where the epiphyseal plate is found in long bones and smaller bones ?
- long bones found on each extremity
- smaller bones e.g. phalanges found only at one extremity
What regions are each myotome divided into ?
- small dorsal region - epimere
- larger ventral region - hypomere
Musculature of the limb is derived from where ?
myogenic cells that migrate into the very early limb bud from the (hypomere)
What’s the difference between the extensor and flexor compartments of the upper and lower limb ?
- upper limb : Flexor = anterior, extensor = posterior
- lower limb : flexor = posterior, extensor = anterior
what happens to limbs during 7th week
rotate in opposite directions
- How does the upper limb rotate during 7th week ?
- where do the extensor muscles lie ?
- where do thumbs lie ?
- rotates 90 degrees laterally
- extensor muscles lie on lateral and posterior surface
- thumbs lie laterally
- How does the lower limb rotate during 7th week ?
- where do the extensor muscles lie ?
- where does the big toe lie ?
- approx 90 degrees medially
- anterior surface
- medially
What happens to thumbs + elbows, soles + knees before and after rotation ?
before rotation
* thumbs up & elbows out
* soles facing (up) & knees out
after rotation
* thumbs out & elbows down
* soles down & knees up
What does limb rotation cause the originally straight segmental pattern of lower limb innervation to do ?
twist into a spiral
List 6 limb defects to know related to limb devleopment
- syndactyly
- polydactyly
- synpolydactyly
- amelia
- meromelia
- thaldiomide defects: phocomelia , amelia
In how many approximately live births does limb malformation occur in ?
6 / 10 000
Limb defects are more common in which limb ?
upper limb than lower limb
Limb defects are …1… and usually ..2… but can be ….3… - included (thalidomide)
- rare
- hereditary
- teratogen
What condition is syndactyly ?
2 or more digits are fused together
What’s the difference in the following syndactyly?
1. simple
2. complex
3. complicated
- fingers joined by skin and soft tissue only
- underlying bones joined together
- extra bones and abnormal tendon and/or ligaments
What is polydactyly (hyperdactyly) characterised by?
supernumerary fingers and/or toes
What may polydactyly result from ?
defective development during anterior - posterior patterning of developing limb
What are the 2 possibilites of appearance of polydactyly ?
- isolation (non-syndromic)
- associated with other birth defects as a part of a syndrome (syndromic)
What is synpolydactyly ?
rare limb deformity showing a distinctive combination of syndactyly and polydactyly
synpolydactyly is assoicated with mutation in what gene ?
Hox D13
Many of the human genetic defects causing limb malformation are the result of mutations affecting …..1…. pathway or the …2.. genes
- Shh signalling pathway
- Hox
What is the limb defect amelia ?
an extremely rare birth defect marked by the absence of one or more limbs
what is the limb defect meromelia characterised by ?
partial absence of one or more limbs
Limb deficiencies have been known to be caused by what list 4 possible causes?
- chromosomal abnormalities
- genetic disorders
- environmental exposure in utero
- complication of chorionic villus sampling
What was thalidomide a drug treatment used for conditions in the 1950s ?
colds, flu, nausea, morning sickness in pregnant women
thalidomide is a potent what ?
teratogen
What are the classical defects associated with thalidomide-induced birth defects ?
- phocomelia (seal limb) = hands and feet seem to arise almost directly from shoulder and hip
- amelia (absence of one or more limbs)
What was thalidomide repurposed in 1998 ? based on what ?
orphan drug for complicaitons of leprosy based on its ability to inhibit the synthesis of the proinflammatory TNF-alpha
What has thalidomide been repurposed as ?
- orphan drug for complications of leprosy
- first-line treatment for multiple myeloma
- potential repositioning for treatment of severe cases of COVID-19
