May23 M1-Embryonic development of vertebral column and limbs 2 Flashcards
what is called the primary curvature of the spine during development
thoracic and sacral C-shaped curvatures seen during fetal development
what is the secondary curvature of the spine
postnatal curvature resulting from lifting the head and walking
what’s a normal thoracic spine curvature
kyphosis, but up to 40-45 degrees. more than that is spinal deformity (abnormal)
most common cause of kyphosis in adults
osteoporosis (much more common in women than men due to losses of estrogen in menopausal and postmenopausal women
(important) important component in vertebral column in how its length changes with age
- IV discs. make up 15-20% of its total length
- they regress with age
- therefore, height reduces with age
spinal cord position relative to the spine vertebral column in fetal phase
- spans hole length of vertebral column
- spinal levels are near their vertebral levels (behind)
what happens to spinal cord position relative to the spine vertebral column as you grow
- vertebral column gets longer BUT spinal cord already reached its final length*
- vertebral column grows downwards (bones increase in size) so spinal cord is displaced upwards relative to the vertebral levels
- curvatures are also forming in vertebral column, so even more displacement upward
dura mater is where around spinal cord
always spans its whole length at all ages
what happens to spinal levels positioning after this displacement upward of spinal cord
- each spinal level is still at its vertebral level (but has to reach further down)
- the lower levels are now surrounded with CSF which fills the dura mater
lower end of the coccygeal spinal cord at birth and clinical significance
vertebral level L2.
do a LP lower than that in newborn.
lower end of coccygeal spinal cord as you grow
becomes vertebral level L1. because vertebrae get longer.
what is found below the L1 vertebral level in the grown spinal cord
filum terminale (spinal nerves) surrounded by dura and pia mater. these nerves go down to the coccyx. *this is called cauda equina*
why is it ok to do an LP in the cauda equina (below L1) in the adult
the spinal nerves will just move apart when doing the puncture, won’t damage anything
consequence of Pax-1 knockout on the spine (TF expressed by sclerotomal cells for bone and cartilage formation)
- no ventral vertebral structures
- you get associated dorsal aspect anomalies
- this dorsal aspect anomaly is SPINA BIFIDA (a bifid spinous process)
- YOU STILL HAVE NORMAL VERTEBRAL ARCHES*
(imp) Pax-1 is important in the formation of what structures + impact of haploinsufficiency in Pax1
- vertebra
- centrum
- IV discs
- so haploinsufficiency of Pax1 affects the formation of these*
what’s Klippel-Feil syndrome
a disease where SOME patients have a mutation in Pax-1 (not all bc this disease as a heterogenous etiology)
-short neck due to Pax-1 abnormality causing vertebrae to fuse rather than have discrete vertebrae and IV discs
what is the structure that surrounds the notochord after the sclerotomal cells did their job
the centrums (bodies of each vertebra.). remember IV discs are between the centrums and notochord will be nucleus pulposus
what does the centrum do as the notochord regresses
it has two centres of chondrification (symmetrical) that will unite as the notochord regresses
this symmetrical formation around the notochord is necessary
what happens in centrum and notochord in Pax1 haploinsufficiency (of sclerotomal cells one one side)
hemivertebra. one side more developed than the other (failure of half of the vertebra to form)
hemivertebra is the most common cause of _________
congenital scoliosis (structural scoliosis) = lateral and rotational curvature of the vertebral column
structure of the vertebra and ribs around a hemivertebra
- on the other half that misses half of the vertebra (on the deficient side), the vertebra above and below the hemivertebra will touch
- rib squeezing also happens
summary of vertebra formation
- ventral side = SHH (of notochord) goes to sclerotomal cells and they express Pax1
- dorsal = BMP4 influences Pax expression and the top lamina (from roof plate) forms the spine (this event fails = spina bifida)
normal closure of the neural tube
meninges, neural tube, cartilagenous vertebral lamina and skin come over and close
why spina bifida if the neural tube doesn’t close
- if doesn’t close, you have no roof plate
- no roof plate = no lamina formed
- no fusion and get spina bifida
diff spectrum of anomalies in spina bifida
can be as bad as a neural tube that is completely open with no vertebra and an open skin
bump on back of baby in spina bifida: what is it called
can be a meningocoele or a meningomyelocoele + one type with the meningocoele can have club feet
spina bifida occulta is what (occulta = hidden)
tuft of hair in lumbar region indicating the possibility that the closure was abnormal and possibly other deleterious effects. but everything is intact
- NORMAL ventral aspect
- ALMOST COMPLETE dorsal aspect but is ABNORMAL
spina bifida with meningocoele is what
- as you go to the back, ventral ok then centrum then dorsal lost then spina bifida
- looping of meninges and skin out (DEFECT IN BONE llowing the fluid to balloon out)
meningomyelocoele (a type of spina bifida) is what
- meninges blew out backwards
- whole spinal cord and nerves pushed out
- ballooning of spinal region with underlyhing meninges containing CSF
- more vulnerable at birth
what happens in lateral plate mesoderm
gut forms there
where the limbs will form
on the lateral plate (somatopleure) which is distal to the dermo-myotome
cells of dermo-myotome go where
some go to the spine and some go to the limb (so somites contribute to vertebra AND upper limb)
phases of formation of limbs from the dermomyotome + time frame for that
- upper limb bud (day 27)
- lower limb bud (day 29)
- limb vessels
* all this between day 24 and da7 27*
why the ULB forms 2 days before LLB
bc of cranio-caudal gradient of formation of embryogenesis
exogenous factors that can affect lumbar development
- drugs and anti-nauseating agents taken by the mother. they’re toxic
- if taken early in gestation, you have no limbs
- if taken later in gestation, the embryo has limb anomalies
- the limb bud phase is critical (24-36 days)*
amelia def + broad causes
complete absence of extremities (limbs)
environmental and genetic causes
meromelia def
absence of parts of an extremity
hemimelia def
distal segment of an extremity is missing
phocomelia def
intermediate segments of limbs are missing but the distal segments are present
syndactyly def
fusion of digits (persistent webbing between the digits)
most common anomaly of hand and foot
amputation in utero: what’s the cause
- fibrous strands in the amniotic fluid encircle the extremities.
- this constricts the digits and ‘‘amputates’’ them during their development
example of substance that can give phocomelia and limb anomalies if taken by mother or embryo exposed to it during limb bud phase
thalidomide
polydactylyl def
abnormal number of digits (>5)
talipes equinovarus (the new term) (congenital clubfoot before) is what
- foot inverted medially (adducted and plantar flexed)
- baby walks on ankle (talus) rather than foot
some causes and associations of talipes equinovarus
- oligohydramnios (as in Potters syndrome)
- spina bifida
what is the main cause for amputation in utero
amniotic band constriction in amniotic fluid (in the sac)
especially affects joints and joint formation
what happens in amputation in utero
- tissue debris accumulate in amniotic fluid
- go around digits or whole extremity and constrict the vasculature and amputate it
cause of syndactyly
the apoptosis between the digits is not occurring normally
what’s synpodia
- abnormal caudal development involving hypoplastic pelvis + fusion of pelvis and lower limbs together + other things
- 1 in 200 000 prevalence
- mermaid syndrome:
ULB: dermomyotome levels contributing to the dermis (dermatome) and myotome
C5-C8 + T1 (brachial plexus). the corresponding nerves will migrate in UL
(comes from somites bc remember dermomyotome is somites)
spinal levels of lumbo sacral plexus
L4 to S3
one cause of problem in brachial plexus
somites having one segment higher or lower that contributes to the brachial plexus when it shouldn’t
where does the limb bud form + what forms it
- lateral plate mesenchyme
- forms from original mesenchyme from somatopleure + mesenchyme from somite migrating)
important site in the limb bud + what it is
ectodermal ridge. at the tip of the limb bud. is a vulnerable site
- the ectoderm goes around the limb bud and this is a site of thickened ectoderm
- site of ectodermal-mesenchyme rejection (only happening there)
2 sources of mesenchyme for the limb bud
- somatopleure
- somites
first interaction between mesoderm and ectoderm (first ectoderm-mesenchyme rejection) is triggered by what
fibroblast growth factor 7 and 8 (FGF7 FGF8)
effect of mutation of FGF7 or FGF8 at stage of ectodermal ridge
no limb formation (amelia) (some toxic drugs can also cause that)
name of the region of early ectodermal-mesenchymal interactions
apical ectodermal ridge
what happens at the ectodermal ridge
the mesenchyme there is induced and then produces scatter factor (a ligand that diffuses in the mesenchyme)
what scatter factor does
- acts on myoblasts with c.Met receptor, from the somites of C5 to T1 which will come to the limb bud and accumulate in the dorsal limb bud
- the dermatomes will also do that
structures that the limb bud takes with it as it grows (and that follow it)
nerves from spinal levels C5 to T1
limb bud in a culture dish will form what
forms a limb bud with primordial cartilage and bone
growth center of the limb bud
the apical ectodermal ridge (which is the tip). and is also the most vulnerable portion
what the AER does
- its cells have gap junctions
- the cells control the underlying mesenchyme (premature stem cells of mesenchyme)
what the premature stem cells of mesenchyme near AER do
interact
2 groups of cells below the ectodermal ridge (thick ridge with gap junctions)
- cranial side = progress zone = the premature mesenchyme stem cells
- caudal side = zone of polarizing activity
substances that the ZPA makes
- SHH
- retinoic acid
- are vulnerable substances*
substances that the progress zone makes
hox genes. produced in a nice sequence of 9 to 13 to segment the whole limb
function of SHH from ZPA
determines how many segments are going to form
sequence of formation of the limb
- AER affects stem cells
- stem cells make the populations of cells that will form the upper limb
- the ZPA will determine how many populations are formed by the stem cells (bc makes SHH)
* populations of cells made in a proximal to distal pattern/outgrowth which ends with the digits*
(imp) 3 induction centers in the limb bud
- AER
- progress zone of stem cells
- stem cells of progress zone making hox genes
how many hox genes
- explains why we have 5 digits. these hox genes form a specific hox code.
hox gene responsible for the ultimate defining characteristics seen in the distal digits
hox 13
hox9 expressed from where to where (ULB as example)
scapula to phalanges
hox10 expressed from where to where (ULB as example)
humerus to phalanges
hox11 expressed from where to where (ULB as example)
forearm (ulna and radius) to phalanges
hox12 expressed from where to where (ULB as example)
wrist (carpals) to phalanges)
hox13 expressed from where to where (ULB as example)
phalanges
molecular causes of polydactylyl
- an excess of SHH (+ remember SHH comes from 2 sources: notochord and ZPA)
- duplication of one or many hox genes
next step after growth of the limb bud
- rotation of the limb bud
- redistribution of the myotome and dermatome components
limb bud position before and after the rotation at 50 days
- before = palms turned inwards and feet too
- after = outwards rotation. palms and hands now in anatomical position
consequence of the limb bud rotation at 50 days
- causes myoblasts and nerves to migrate and reach specific compartments
- nerves coming in from the brachial plexus mix up
one thing that can happen if the rotation is incomplete in the feet
keep their inward rotation = club feet
dermatome def
regions of skin supplied by somitic mesenchyme (from somites), which is supplied by sensory nerves from dorsal root ganglia (DRG) and functional spinal cord segments C4 to T1.
one important dermatome to remember
C6: thumb region and proximal portion of the forearm
main nerves in brachial plexus and those contributing to C6 dermatome over the thumb and proximal forearm
- musculocutaneous n. (ant lat): contributes to C6 dermatome
- radial n. (post): contributes to C6 dermatome
- median n. (ant middle)
- ulnar n. (ant med)
what happens if C6 is infected or cut
no sensory innervation ot C6 region
best region to test the dermatomes
the hand (is more sensitive than in the arm)
structure supporting the base of the brain and associated problems
- cartilage and endochondrium
- specific mutations can lead to problems in these
foramen magnum is what + importance
- hole in the back in the bottom of the skull, lets the spine pass
- not well formed = hindbrain is afected
- can be lethal or hydrocephalus
cause of foramen magnum not forming well
an anomaly in the formation of the occipital bone
consequence of abnormal cartilage model in the vertebrae
- vertebrae are initially cartilage which will be replaced by bone
- abnormal cartilage model = lordosis, kyphosis + problems in subsequence bone formation
last thing to form in the back in the fetus
cartilage, defect related to spina bifida
type of bone supporting the brain
endochondral bone
how endochondral bone arises in the brain
plates of bone direct mesenchymal cells to form osteoblasts
which cells form bone in the head and neck
NCCs (are pluripotent)
bones of the skull + development
- frontal, 2 parietal and occipital bones
- separated by sutures
- grow out centrally and fuse in the midline
- this fusion takes time and is complete at 2 years old
function of the bones of the skull in the fetus
- help passage of head through the small birth canal
- parietal bone on side is flat so helps that
- this is why the fusion takes a long time*
cranial synostosis is what + example where sagittal suture fuses first
- fusion before birth while brain growing
- sagittal suture fusing first = elongated head
cranial synostosis is related to what mutation
FGF3R mutation
2 phases of skull bone formation
- endochodrium
2. intramembranous bone formation
which suture gives serious problems if it fuses first
coronal suture (the suture at the front between the frontal bone and the two parietal bones)
