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

Abstract

The morphogenesis of the brain is governed by synaptogenesis. Synaptogenesis in turn is determined by cell adhesion molecules, which bridge the synaptic 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 cadherins, play a decisive role. Surprisingly, the genetic control of the protocadherins is very similar to that of the immunoglobulins. There are three sets of variable (V) genes followed by a corresponding constant (C) gene. Applying the rules of the immunoglobulin genes to the protocadherin genes leads, despite of this similarity, to quite different results in the central nervous system. The lymphocyte expresses one single receptor molecule specifically directed against an outside stimulus. In contrast, there are three specific recognition sites in each neuron, each expressing a different protocadherin. 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 layers, permitting an enormous number of different connections and restraints between neurons. This network is one module of the central computer of the brain. Since the V-genes are generated during evolution and V-gene translocation during embryogenesis, outside stimuli have no influence on this network. The network is an inborn property of the protocadherin genes. Every circuit produced, as well as learning and memory, has to be based on this genetically 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.

Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders

“…First, they are members of the PCDH family, which is known to play a major role in synapse recognition and neuronal path finding during brain development [Hilschmann et al, 2001]. Second, PCDH11Y is one of the rare genes located on the Y chromosome with a strong regulated expression in the brain [Blanco et al, 2000;Blanco-Arias et al, 2004].…”

Origin and Evolution of the Brain

“…Protocadherins, in particular, have an enormous potential for diversification because their genes contain variable and constant regions like the genes of the immunoglobulins. They could, therefore, provide the building blocks of a neural system that is capable of learning and memorizing, and, like the immune system, can cope with virtually everything, even the unexpected (Hilschmann et al 2001). This suggests that the chemoaffinity hypothesis of Roger Sperry should be re-formulated in terms of a code.…”

Diversity of the cadherin‐related neuronal receptor/protocadherin family and possible DNA rearrangement in the brain

“…Thus, combinatorial expression, gene regulation, trans ‐splicing and somatic mutations of the CNR/Pcdh family may predetermine the formation of the complex neuronal network, and this blueprint may select against individual responses. In another paper, a three‐dimensional predetermination in the neural networks has been proposed by use of the CNR/Pcdh α, Pcdh β and γ family genes (Hilschmann et al . 2001).…”