Introduction

From a practical point of view, the pathology of peripheral nerves falls into two main categories: (a) peripheral neuropathies, which are diagnosed and treated by physicians and for which an elective nerve or muscle biopsy may be performed as a diagnostic procedure rather than as a therapeutic exercise, and (b) tumors and traumatic lesions, which are removed surgically mainly as a therapeutic measure to alleviate symptoms.

For the diagnosis of peripheral neuropathies, a detailed knowledge of the structure, immunohistochemistry and ultrastructure of peripheral nerves, and clinicopathological correlations is essential. The diagnosis of tumors and traumatic lesions, conversely, relies more on identifying the cellular components within the lesion and their interrelationships. This chapter, therefore, concentrates first on how to identify different cellular components in normal peripheral nerves and, second, on how knowledge of the normal structure of peripheral nerves can be used to identify and assess pathological lesions.

Development of the Peripheral Nervous System

The first anatomical evidence of nervous system differentiation is the neural plate, which develops as a thickened specialized area in the middorsal ectoderm of the late gastrula stage of the developing embryo. This zone later becomes depressed along the axial midline to form a neural groove that folds inward to form the neural tube. Before fusion is completed, groups of cells become detached from the lateral folds of the neural plate to form the neural crests. Anteriorly, neural crests are located at the level of the presumptive diencephalon and extend backward along the whole neural tube.

The neural crest yields pluripotent cells endowed with migratory properties. In the peripheral nervous system, the neural crest is the source of neurons and satellite cells in the autonomic and sensory ganglia; ectodermal placodes may also give rise to ganglion cells in the cranial region. Schwann cells are also derived from the neural crest. Migrating pluripotent neural crest cells and their subsequent development is determined and progressively limited, perhaps by the inductive effect of neuregulins and their receptors erbB2 and erbB3, by environmental factors, and by relations with other cell types . The transcription factor Sox-10, that is initially expressed in the earliest migrating neural crest cells, appears to be intimately involved in the development of Schwann cells from the neural crest. Interestingly, the major myelin protein, P0, is also a transcriptional target for Sox-10 .

Many of the events that occur during the later stages of development of peripheral nerves are recapitulated during the regeneration that follows nerve damage in postnatal life. Developing neuroblasts of the dorsal root ganglia (posterior sensory root ganglia) extend neurites both centrally into the neural tube and toward the periphery. Developing motor neurons in the anterior lateral parts of the neural tube extend their neurites toward the periphery. Schwann cells derived from the neural crest become associated with the developing peripheral nerves and eventually form myelin around many of the axons. The proximal portions of the anterior horn cell axons and the central axons of the sensory ganglion cells are myelinated within the neural tube by oligodendrocytes.

Growth of Axons

One of the major questions that has been raised is how neuronal processes grow over long distances and arrive at specific terminal regions. Genetic determinants, growth factors, and the extracellular matrix appear to play important roles in the appropriate guidance of neuronal processes. In 1909, Santiago proposed the concept of neurotrophic substances to explain the directionality and specificity of axonal growth in the developing nervous system, but it was not until the 1960s that nerve growth factor (NGF) was discovered by Rita Levi-Montalcini and Stanley Cohen, as a target-derived neurotrophic factor that supports the survival and differentiation of sensory and autonomic ganglia in the peripheral nervous system (6).

Nerve growth factor is a protein composed of three subunits alpha (α), beta (β), and gamma (γ) but only the β-NGF has nerve growth promoting activity. Beta-NGF in humans is a 14.5 KDa polypeptide, γ-NGF is an arginyl esterase, whereas the function of the α subunit is not known. Other substances that participate in axon growth are members of the NGF family [such as brain-derived neurotrophic factor (BDNF)]; neurotrophins 3 (NT-3), 4/5 (NT-4/5), and 6 (NT-6); semaphoring-3A, neuropilin-1, and ephrin . The tips of growing axons possess multiple surface receptors for soluble and bound molecules that provide information for the axons' growth course . Nerve growth factor interacts with the NGF receptor on the surface of the axon and promotes motility of the growing tip of the axon by interaction with the cytoskeleton of the cell. Mitochondria, neurotubules, neurofilaments, actin filaments, and some cisternae of smooth endoplasmic reticulum are incorporated into the axonal growth cone by axoplasmic flow. In addition to its growth promoting properties, NGF also promotes the early synthesis of neurotransmitters.

Schwann cells in the developing nerve produce NGF and possess NGF receptors on their surface membranes, but expression of these receptors diminishes markedly as the peripheral nerve matures. As NGF binds to Schwann cell receptors and becomes concentrated on the surface of the primitive Schwann cell, it provides a chemotactic stimulus for growing axons . Failure of trophic interactions between the target organ and its innervation may result in nerve dysfunction. Indeed, cases of human neuropathies have been attributed to deficiency of neurotrophic factors; important data that provides a rational basis for the clinical use of neurotrophic agents in peripheral neuropathies.

The extracellular matrix also plays an important role in axonal growth and guidance. The tip of the growing axon has receptors for adhesion to extracellular substances such as collagen, fibronectin, laminin, and entactin; binding of extracellular components to these receptors promotes elongation of axons and stimulates cytoskeletal protein synthesis and therefore cell movement and axon growth. Some of these extracellular components are found within or near basement membranes surrounding Schwann cells .