Embryology

Aaron Dailuski

The development of the extremities requires precise temporal and spatial regulation of multiple signaling pathways. Understanding of the basic molecular and developmental events is helpful to understanding the pathoanatomy of congenital limb differences and possible comorbid conditions in patients with other developmental anomalies.

I. Early Limb Formation

The upper limb buds first develop by day 26 following fertilization (fourth week of gestation). Most of the critical patterning events occur between days 26 and 42 following fertilization, making the first trimester the critical point for upper limb development. When an interruption in the normal development process occurs, anomalies associated with other structures developing during this time period may be seen, which explains the occurrence of multiple anomalies.

Early limbs have a paddlelike shape and first have the proportional appearance of a human extremity by the eighth week of gestation. Each limb has a core of mesenchymal tissue from the somite (which develops into muscle) and the lateral plate (eventual connective tissues of the limb) with an outer shell of ectoderm. After initial outgrowth, the limbs rotate along their longitudinal axis to their final positions.

II. Molecular Events of Early Limb Development

Early limb development occurs with highly regulated molecular mechanisms controlling each of the three axes.

Longitudinal (proximodistal or PD) outgrowth, which controls overall limb length.
Anteroposterior (AP) development occurs in the radioulnar plane.
Dorsoventral (DV) axis.

Although there are key regulators for each of these independent axes, coordination between the three axes exists to ensure the development of an upper extremity with proper proportions.

A. Proximodistal Growth

The key anatomic structure to early longitudinal growth of the limb is a ridge of ectoderm at the junction of the dorsal and ventral surfaces known as the apical ectodermal ridge (AER). The tissue of the AER produces a signal, which is both necessary and sufficient to promote longitudinal growth of the limb. The primary factors promoting longitudinal growth produced by the AER are members of the fibroblast growth factor family.

B. Anteroposterior Development

Identity of digits along the AP (radio-ulnar, pre-axial-postaxial) axis is crucial for normal limb development and function. For example, the radial most digit, the thumb, has clear morphologic differences from the remaining digits. The tissue responsible for setting up AP axis in both the upper and lower limbs is a region of tissue along the posterior margin of the limb paddle called the zone of polarizing activity (ZPA). The ZPA tissue expresses the secreted signaling molecule sonic hedgehog (Shh), which alone can provide the necessary signal for normal AP development. The primary function of Shh from the ZPA is the coordination of AP development; however, its signal also affects development along the PD and DV axes coordinating spatial growth along all three axes.

C. Dorsoventral Patterning

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