Musculoskeletal System: Limbs
Introduction
Limb
development has been studied in great detail, although it is not entirely clear
how it is initiated. The mechanisms by which the cells of the early limb are
organised, and the fates of those cells, have been explored for decades, as
aberrations of these processes cause gross limb abnormalities.
Limb buds
Cells in the
lateral mesoderm at the level of C5–T1 begin to form the upper limb buds at the
end of the fourth week and they are visible from around day 25. The lower limb
buds appear a couple of days of later at the level of L1–L5 (Figure 26.1).
Each limb
bud has an ectodermal outer covering of elium and an inner mesodermal mass of mesenchymal
cells.
A series of
reciprocal interactions between the underlying mesoderm and overlying ectoderm
result in the formation of a thickened ridge of ectoderm called the apical
ectodermal ridge (AER; Figure 26.2). This ridge forms along the boundary
between the dorsal and ventral aspects of the limb bud.
The AER
forms on the distal border of the limb and induces proliferation of the
underlying cells via fibroblast growth factors (FGF), inducing distal outgrowth
of the limb bud. This area of rapidly dividing cells is called the proliferating
zone (PZ; Figure 26.2). As cells leave the PZ and become further from the
AER they begin differentiation and condense into the cartilage precursors of
the bones of the limb. Endochondral ossification of these bones is described in
Chapter 23.
Patterning
within the early limb bud controls the proliferation and differentiation of
mesenchymal cells, forming the structures of the limb. The AER controls the
proximal distal axis, for example.
A group of
cells in the caudal mesenchyme of the limb bud act as a zone of polarising
activity (ZPA; Figure 26.3), secreting a morphogen that diffuses cranially
and themselves contributing to development of the digits. The ZPA has a role in
a cranial caudal axis (i.e. specifying where the thumb and little finger form;
Figure 26.3).
The dorsal ventral
axis is controlled by signals from the dorsal and ventral ectoderm. These
signals specify which side of the hand the nails should form on and which side
the fingertips, for example.
Disruption
of these patterning signals (and others) causes limb malformations.
During weeks
6 and 7 (development of the lower limbs lags behind that of the upper limbs)
the distal edges of the limb buds flatten to form hand and foot
plates. Digits begin to develop as condensa- tions of mesenchymal cells
clump together to construct long thickenings (Figure 26.4). Localised
programmed cell death between these digit primordia splits the plate into five
digital rays, and the mesenchymal condensations develop to become the bones and
joints of the phalanges (Figures 26.4 and 26.5).
Cells from
the dermamyotomes of somites (see Chapter 22) at the levels of the limb buds
migrate into the limbs, and differentiate into myoblasts. They group to form
dorsal and ventral masses, which will approximate to the muscles of the flexor
and extensor compartments of the adult.
Motor
neurons from the ventral rami of the spinal cord at the levels of the limb buds
(C5–T1 for the upper limbs, L4–S3 for the lower limbs) extend axons into the
limbs, following the myoblasts (Figure 26.6). Control of this axon growth also
occurs independent of muscle development, however. Dorsal branches from each
ventral ramus pass to muscles of the dorsal mass (extensors), and ventral
branches from each ventral ramus pass to the ventral mass (flexors). Also, more
cranial neurons (C5–C7 in the upper limb, for example) pass to craniodorsal
parts of the limb bud, and more caudal neurons (C8–T2) pass to ventrocaudal
parts.
As axons
enter the limb bud they mix to create the brachial and lumbosacral plexuses
during this development stage, before the axons continue onwards to their
target muscles. Branches combine to form larger dorsal and ventral nerves, eventually
the radial, musculocutaneous, ulnar and median nerves in the upper limb, for
example. The radial nerve forms from dorsal branches, as it is a nerve that
innervates the extensor muscles of the upper arm and forearm.
The muscle
groups, initially neatly organised, fuse and adult muscles may be derived from
myoblasts from multiple somites. Likewise, axons of the dorsal root ganglia
initially carry sensory innervation from the skin of the limb in an organised
pattern of dermatomes.
The upper
limb begins to become flexed at the elbow, and the lower limb develops a bend
at the knee in week 7. The limbs also rotate, transforming from a simple,
outwardly extending limb bud to a more recognisable limb shape. The upper limb
rotates laterally by 90° and the lower limb rotates medially by 90° (Figure
26.7). By the end of week 8 the upper and lower limbs are well defined, with
pads on the fingers and toes. The hands meet in the midline, and the feet have
become close together.
With the
rotation and bending of the limbs, and the fusing of early muscles, the
patterns of muscle innervation and dermatomes are disrupted and produce the
adult patterns (Figures 26.7–26.9).
Clinical relevance
The period
of early limb development of weeks 4 and 5 is susceptible to interruption by
teratogens, as seen in the thalidomide epidemic of congenital limb
abnormalities of the 1950s and 1960s. The earlier the teratogen is applied to
the foetus, the more severe the developmental defects.
Achondroplastic dwarfism is caused by a mutation
in the fibroblast growth factor receptor 3 gene (FGFR3). FGF signalling
via this receptor is involved in growth plate function, and disruption of this
causes limited long bone growth and disproportionate short stature.
Meromelia describes the partial
absence of a limb, and amelia the complete absence of a limb. Phocomelia
refers to a limb in which the proximal part is shortened, and the hand or
foot is attached to the torso by a shortened limb.
In polydactyly
an extra digit, often incomplete, forms on the hand or foot. Ectrodactyly
describes missing digits, and often lateral digits forming a claw‐shaped
hand or foot. A hand or foot with brachydactyly has shortened digits. A
person with syndactyly has webbed digits as the interdigital cells
failed to apoptose normally.
