Plasminogen activator–plasmin system and neuronal migration

Abstract

Neuroontogenesis results from a synchronized series of elementary events including cellular proliferation, migration, differentiation, recognition and death. Neuronal migration is a key step in neural morphogenesis since inadequately located neurones may not establish the appropriate connections and this may lead to neuronal death or to functional deficit of synaptic circuits. Impairment of neuronal migration has been implicated in human pathology¹ and well documented in animal pathology, such as the weaver mutation in mice². The cerebellum of small rodents is particularly well suited for the study of neuronal migration because a subpial neuronogenesis occurs postnatally. The subsequent inward migration of postmitotic neurones (mostly granule cells) has been studied using classical neuroanatomical methods, such as the Golgi stain³, and autoradiography after systemic injection of ³H-thymidine⁴. Systematic ultrastructural investigation of neuronal migration at different levels of the central nervous system and in different species led Rakic to propose the radial glia hypothesis—that neurones migrate along radial glia cells which serve as guides during migration⁵. The observation that neurones migrate inside a densely packed neuropile has prompted us to consider the possible role of extracellular neutral proteolysis during neuronal migration. We have focused on the plasminogen activator (PA) serine proteases because these enzymes are known to be involved in several phenomena that involve cell migration or tissue remodelling⁶. The usual substrate for PA is plasminogen, which is converted to plasmin, although other substrates may exist⁷. We report here that both PA and plasmin are released by cultived 7-day-old rat paraflocculus, but not by 1-month-old or adult rat paraflocculus (that is, after granule cell migration), and that inward migration of cerebellar granule neurones, which account for 95% of the cells in adult cerebellum, can be inhibited by inhibitors of the PA–plasmin system.