13. Limb Devo Flashcards
areas of somatic mesoderm located on each side of the
embryo.
The Limb Fields
Due to differential expression of_______ genes, the limb fields are localized at distinct axial levels, one for the upper limb and one for the lower limb
Hox
Specific transcription factors are expressed within the upper limb_____ and the lower limb ______
(Tbx5)
Tbx4 & Pitx-1
Limb bud outgrowth is initiated by signaling molecules
_______originating in the _______ mesoderm.
(FGF & Wnt)
intermediate
Limb bud outgrowth is initiated by signaling molecules
(FGF & Wnt) originating in the intermediate mesoderm. These signals induce ______ expression in the appropriate areas of ________ resulting in limb bud formation.
FGF 10
lateral plate mesoderm
forms skeletal elements, fibrous connective tissue and
dermis of the skin (probably vascular endothelium and smooth muscle)
Somatic mesoderm
forms the epidermis of the skin
Surface Ectoderm
migrates into the limb bud forming the skeletal muscle
Somitic (somite derived) mesoderm –
Nerve fibers from ________ of spinal nerves migrate into the limb and become surrounded by neural crest-derived Schwann cells.
ventral primary rami
Limb development occurs along three axes. Limbs elongate and limb segments are formed along the _______ axis.
proximal-distal
Muscles and nerves are organized in
compartments along a _______ axis.
dorsal–ventral
Digits are arranged along an _______ axis.
anterior-posterior
After limb outgrowth is initiated, Fgf 10 produced by the somatic mesoderm of the
bud initiates the secretion of______ (also Fgf4 & 2) in the distal ectoderm. This results in a thickening of the distal ectoderm called the _________
Fgf 8
apical ectodermal ridge(AER).
What defines the location of the ridge at the boundary between the dorsal and ventral surfaces of the limb? T
Differential gene expression in the dorsal and ventral surface ectoderm
acts as a signaling center for the underlying
mesenchyme (originating from somatic mesoderm).
AER
Signals from the AER (primarily Fgf 8) induce the adjacent mesenchyme to proliferate, which creates a
pool of mesenchyme cells that enable the limb ______
to elongate.
_____ signals also inhibit mesenchyme differentiation and is secreated from the mesenchyme adjacent to the AER
to maintain AER function until all limb segments
are formed.
Fgf
Thus a positive Fgf feedback loop occurs between the mesenchyme (Fgf 10) and the AER (Fgf 8).
The arrangement of the digits is achieved by signaling from the_________ on the posterior border of the limb just proximal to the AER.
Zone of Polarizing Activity (ZPA)
The ZPA is an area of somatic mesenchyme on the posterior side of the limb bud that secretes
Sonic hedgehog (Shh)
has been shown to mimic the action of Shh.
Retinoic acid
Expression of Shh from the ZPA initiates the expression of a subset of the Hox genes in the posterior
mesoderm… how does this cause normal digit formation
Expression occurs in an overlapping nested fashion. This expression pattern of Hox genes as well as other signaling molecules
The flat digital plate contains condensations of mesenchyme representing each digit called _____
digital rays
The phalanges and joints will form from digital rays and initially they are joined together by a web of condensed mesenchyme. The AER in the web areas disappears and
triggers apoptosis within the web mesenchyme. This results in digit separation. The AER remains at the
distal tip of the digital ray until all parts of the digit have formed.
How do we get vascular supply to developing muscles in the limbs?
Sprouts from several intersegmental arteries enter the limb bud and form a vascular network within the mesenchyme. Eventually one intersegmental
dominates as the primary axial artery. During development, the vascular network is remodeled into the mature vascular arrangement.
The Preaxial channel in the upper limb becomes the ______, while that in the lower limb becomes the
cephalic vein
saphenous vein
Nerve trunks from the _______ grow into thelimb bud and associate with the forming skeletal muscles, vessels and skin.,,,signals from mesenchyme at the base of the limb bud appear to direct nerve ingrowth.
forming brachial and lumbosacral plexuses
Overall dorsal and ventral pattering is set up by
competing signals for the dorsal and ventral ectoderm.
The upper limbs rotate______ and the lower limbs rotate _________
laterally
medially
On average limb defects occur in
two per thousand live births
When is limb development most sensitive to teratogenic development?
between the 4th to 9th weeks of development.
is a potent teratogen that causes significant limb defects.
Thalidomide
What is the difference between a defect and a deformation?
defect = morphological abnormality resulting from abnormal developmental mechanisms or processes, thus it is inherent to the process of development.
deformation=abnormal form, shape or position of a normally formed body part. Mechanical forces that impact the child as it develops cause deformations.
These types of limb defects would be similar to
amputations along the proximal–distal axis. That is segments or parts of segments are missing distal to the “amputation”.
Transverse Type –
The most severe form of Transverse type is
the absence of an entire limb, a condition called
Amelia
Transverse type condition where only a segment or part of a segment is missing, e.g. a forearm and hand or a foot. These types of truncation are called
Meromelia.
This subset includes defects were there are parts
missing within one or more segments of the limb. For example, the radius and
some digits, along the anterior-posterior axis may be missing or the fibula may be absent.
Longitudinal Type
where the missing parts are in the median aspect of the distal limb segment, such as the middle digits, which creates a “lobster claw-like” deformity.
Oligodactyly
(seal limb) where the most distal limb segment(s) is (are) attached to the limb girdle, e.g. the hand is
attached to the shoulder girdle or the foot to the pelvic girdle.
Phocomelia
Syndactyly and Sirenomelia are both examples of
Failure of Differentiation or Separation of Limb Parts
Digits may be completely or partially fused. Fusion may involve only the skin or may include fusion of the bones.
Syndactyly
fusion of complete lower limbs or lower limbs represented by a conical stump, is the most extreme case of this type of anomaly.
Sirenomelia
a condition where there is one or more extra digits. This may occur unilaterally or bilaterally.
Polydactyly
where several digits as well as part of the hand or foot are duplicated.
Diplopodia
bands of amnion can break free and wrap around portions of the fetus. Amniotic bands can wrap around a normally formed limb causing a severe constriction or amputation
Congenital Constriction Band Syndrome
Clubfoot (also called talipes) is any defect involving the ____ bone.
talas
the foot is plantar-flexed (like a horse’s
foot), inverted and adducted (varus). This type is twice as common in boys as in girls.
talipes equinovarus,
Cause of Clubfoot
Some believe that most instances of
clubfoot represent a defect the repair of which may involve some surgical as well
as casting procedures. A clubfoot may also be acquired when the foot becomes
located in an abnormal position within the uterus. Clubfoot is often isolated but it
is part of some syndromes. Multifactorial inheritance may also play a role.
Developmental Dysplasias: The major problem is that the hip is for some reason
more susceptible to dislocation after birth.
Reasoning for Developmenta Hip Dysplasia
This is compounded by the fact that normally at birth the hip joint is somewhat immature and malleable to aid in
the birth process. The thinking regarding this defect is that the hip joint is more insufficiently formed than usual. Congenital hip dysplasia is often associated
with breech births and with a syndrome of generalized joint laxity.
What conditions during pregnancy and birth may also contribute to developmental hip dysplasias?
Hormones that make the maternal connective tissue soft at childbirth
Pattern of susceptibility for developmental hip dysplasias?
more common in females and may be unilateral or bilateral. The defect tends to run in families
characterized by an undescended scapula.
Normally the scapula is located between T2-T7. In this
deformity it is located at C4-T2. The muscles associated with the scapula are hypoplastic or atrophic which limits shoulder movement and is disfiguring.
The Sprengel Deformity
Sprengle deformity shows a 3:1 predominance in_____. Usually there are associated anomalies of the_____.
males
spine
People with this deformity have a variety of anomalies that include hypoplasia or aplasia of the clavicles, large head, small face, long neck, and a short narrow chest. They also have short fingers and dental problems.
Cleidocranial Dysplasia
Cause of Cleidocranial Dysplasia
defect in Runx-2.
