Several research groups have isolated cell surface molecules from the central nervous system (CNS) in their search for additional cadherin-like molecules necessary for cell-cell interactions. These studies have identified a large number of genes, designated as protocadherins, and cadherin-related neuronal receptors (CNRs). Protocad­herins constitute the largest subgroup within the cadherin family with approximately 80 members. Protocadherins of each family differ in their extracellular domains, which contain up to seven EC domains but share an identical cytoplasmic domain. The cytoplasmic region displays no similarity to those of classical cadherins. Yamagata et al. [19] constructed chimerical molecules containing the extracellular domains of rat protocadherins Pc2 and Pc3 fused to the cytoplasmic domain of E-cadherin in order to prove whether these molecules have adhesion activities like classical cadherins. The chimerical molecules dis­played stronger homophilic cell adhesion than the E-cad­herins. These findings indicate that the EC domains of protocadherins can undergo homophilic interactions, as found for those of classical cadherins, but the functions of the cytoplasmic domains are not identical between those subfamilies. Another member of the protocadherin group, activity-regulated-cadherin-like protein (ARCADLIN), also shows homophilic adhesion activity [19].

      Protocadherins have been identified not only in verte­brates, but also in many lower multicellular organisms. In Xenopus and Zebrafish those proteins are strongly impli­cated in development and in cell movements that drive gastrulation [20].

      In mammals, protocadherins are highly expressed in the nervous system and are far more numerous in the brain than in any other tissue. Throughout brain development, protocadherins show distinct spatiotemporal expression patterns, which relate to the development of the brain into discrete segmental and functional subdivisions and provide a scaffold of adhesive molecules [21]. The OL-protocad­herin is identified from a mouse brain cDNA library and encodes a protein with a unique cytoplasmic region. Its expression is restricted only to a subset of functionally related brain nuclei in the main olfactory system, the lim­bic system and olivocortical projections [22].

      Most genes for the protocadherins are located at chro­mosome 5q31-32 (Table 1), the rest are localized in differ­ent chromosomal regions (Table 2). The three large proto­cadherin clusters on 5q31-32 consist of 52 genes (Pcdh-α, Pcdh-β , Pcdh-γ ). The Pcdh-β cluster comprises tandemly arrayed single-exon genes flanked by individual 5' promo­tors, whereas the Pcdh-α and Pcdh-γ clusters additionally contain, at the distal 3' end, three small exons coding for a cluster-specific constant domain. The variable domains of the Pcdh-α and Pcdh-γ are encoded by the large exons and encompass most of the transmembrane protein, includ­ing a short cytoplasmic tail. Thus, Pcdh-α and Pcdh-γ proteins share a cluster-specific constant domain located at the cytosolic C-terminus that is missing in Pcdh-β pro­teins. Individual transcripts are generated by cis-splicing events [2]. One C-part can be linked to a different V-part. In Pcdh-α clusters there are 15 Vα-parts, in Pcdh-β , 15 functional Vβ -parts and in Pcdh-γ , 22 functional Vγ -parts that can be linked to the corresponding Cα-, Cβ - or Cγ -parts [23-25].

      Another group of protocadherin-type molecules is cadherin-related neuronal receptors (CNRs). The CNRs are single-pass proteins that contain six EC domains, simi­lar to other protocadherins, but have a unique cytoplasmic domain with six cadherin repeats that interact with Fyn tyrosine kinase. Fyn is critical for normal brain organiza­tion and function. The CNRs are located in synaptic junc­tions mainly in the active zone of small and immature synapses. Different neurons express distinct sets of CNR genes. The CNR genes are also organized as a gene clus­ter, which is similar to that of imunoglobulin (Ig) and T-cell receptor genes. The CNR gene cluster contains genes for variable and constant regions. The rearrangement be­tween V- and C-regions can produce three types of CNR. Every neuron expresses typical sets of CNR protocad­herins that can bind to a particular neuron. Therefore, diversity and regulation of the CNR expression may be required for establishing diversity and order organization of the CNS.

      The large extracellular protein Reelin is produced by specific neurons, the Cajal-Retzius cells. The reelin gene is conserved in many vertebrate species, including humans [26]. During development of the cortex, the functional CNR proteins recognize extracellular Reelin, which binds to the CNR. This complex interacts with Fyn kinase through a cytoplasmic adaptor mDAB1. Fyn contains a protein-interaction domain that binds to Asn-Pro-X-Tyr motifs in the cytoplasmic tails of many receptors such as very-low-density lipoprotein receptor. Another target pro­tein of this signaling pathway is p35-CDK5 kinase. The activated p35-CDK5 kinase associates with N-cadherin and suppresses its adhesive activity by reducing its interac­tion with β-catenin. Thus, CNR can regulate the adhesion of the classical cadherins and the adhesive specificity of the neuronal cells [1].

Table 1. Pcdh-a, Pcdh-b and Pcdh-g gene clusters