Early events in the histo- and cytogenesis of the vertebrate CNS

Abstract

Development of the vertebrate, viewed on the cellular level, proceeds by sequential steps in which potencies of progenitor cells become progressively and irreversibly restricted. This is known as progression of the major differentiation. Cytogenesis of the CNS may be regarded as one typical example. The period of cytogenesis in the CNS is divided into three consecutive stages. In stage I, the wall of the neural tube is composed solely of matrix cells. In stage II, i.e., the stage of neuronogenesis, some of the daughter matrix cells are determined at the early G1 phase to be differentiated into neuroblasts. The specificity of individual neurons appears to be irreversibly determined at the time of birth of the neuroblasts, as a function of time-and-place of their production. The individual matrix cells that have existed at the very beginning of neurogenesis give birth to a series of progressively different types of neurons in stage II as the major differentiation proceeds. Finally, matrix cells cease to produce neurons. This is the end of stage II. Thereafter, only non-neuronal cells, namely neuroglia and ependymal cells, are produced. This is stage III or the stage of neuroglia production. The sequential nature of the differentiative behavior of matrix cells can be explained by the hypothesis of progressive gene inactivations that accumulate in genomes of matrix cells during development. Different types of neurons are produced from matrix cells at different states of the <<major differentiation>>. Irreversible inactivation of genes progresses during stage II of cytogenesis, and when genes essential for neuronal differentiation are inactivated in matrix cell genome, the cell can no longer differentiate neurons but necessarily produces only non-neuronal elements, i.e., neuroglia and ependymal cells. Thus the consecutive occurrence of stages I, II and III can be understood. Studying pathfinding of spinal neurons, we found that the dynamic behavior of filopodia plays an essential role in guiding and establishing connection to the target cells. By extension, retraction and swinging movements, the filopodia can search for positive cues over an area of 40 μm in diameter. Examining how spinal nerves emerge to find out their target muscle cells in chick embryos, we found that (1) the developmental environment provides an adequate channel between neural arches to the target at the time the neuronis just beginning to send out its axon, (2) the distance between axon tips and the target is short when the axion first grows out. It is almost within a shooting range of the filopodia, and (3) if the filopodia can not directly touch the target cells, the growth cone proceeds and reaches the target within 30 min. These three features can be regarded as triple assurance for perfect pathfinding. Specific surface molecules to assure specific adhesion provide also the fourth assurance. Multiple assurance seems to be a general principle of development for the infallible assembly of morphological and functional organization in a developing CNS.