Genetic Basis of Neuronal Individuality in the Mammalian Brain

The mammalian brain is a complex multicellular system involving enormous numbers of neurons. The neuron is the basic functional unit of the brain, and neurons are organized by specialized intercellular connections into circuits with many other neurons. Physiological studies have revealed that individual neurons have remarkably selective response properties, and this individuality is a fundamental requirement for building complex and functionally diverse neural networks. Recent molecular biological studies have revealed genetic bases for neuronal individuality in the mammalian brain. For example, in the rodent olfactory epithelium, individual olfactory neurons express only one type of odorant receptor (OR) out of the over 1000 ORs encoded in the genome. The expressed OR determines the neuron's selective chemosensory response and specifies its axonal targeting to a particular olfactory glomerulus in the olfactory bulb. Neuronal diversity can also be generated in individual cells by the independent and stochastic expression of autosomal alleles, which leads to functional heterozygosity among neurons. Among the many genes that show autosomal stochastic monoallelic expression, approximately 50 members of the clustered protocadherins (Pcdhs) are stochastically expressed in individual neurons in distinct combinations. The clustered Pcdhs belong to a large subfamily of the cadherin superfamily of homophilic cell-adhesion proteins. Loss-of-function analyses show that the clustered Pcdhs have critical functions in the accuracy of axonal projections, synaptic formation, dendritic arborization, and neuronal survival. In addition, cis-tetramers, composed of heteromultimeric clustered Pcdh members, represent selective binding units for cell-cell interactions, and provide exponential numbers of possible cell-surface relationships between individual neurons. The extensive molecular diversity of neuronal cell-surface proteins affects neurons’ individual properties and connectivities. The molecular features of the diverse clustered Pcdh molecules suggest that they provide a genetic basis for neuronal individuality and appropriate neuronal wiring in the brain.