Musculoskeletal System: Limbs
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.
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).
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.