The immunoglobulin-like genetic predetermination of the brain: the protocadherins, blueprint of the neuronal network

The morphogenesis of the brain is governed by synaptogenesis. Synaptogenesi s in turn is determined by cell adhesion molecules, which bridge the synapt ic cleft and, by homophilic contact, decide which neurons are connected and which are not. Because of their enormous diversification in specificities, protocadherins (pcdh alpha, pcdh beta, pcdh gamma), a new class of cadheri ns, play a decisive role. Surprisingly, the genetic control of the protocad herins is very similar to that of the immunoglobulins. There are three sets of variable (V) genes followed by a corresponding constant (C) gene. Apply ing the rules of the immunoglobulin genes to the protocadherin genes leads, despite of this similarity, to quite different results in the central nerv ous system. The lymphocyte expresses one single receptor molecule specifica lly directed against an outside stimulus. In contrast, there are three spec ific recognition sites in each neuron, each expressing a different protocad herin. In this way, 4,950 different neurons arising from one stem cell form a neuronal network, in which homophilic contacts can be formed in 52 layer s, permitting an enormous number of different connections and restraints be tween neurons. This network is one module of the central computer of the br ain. Since the V-genes are generated during evolution and V-gene translocat ion during embryogenesis, outside stimuli have no influence on this network . The network is an inborn property of the protocadherin genes. Every circu it produced, as well as learning and memory, has to be based on this geneti cally predetermined network. This network is so universal that it can cope with everything, even the unexpected. In this respect the neuronal network resembles the recognition sites of the immunoglobulins.