Vydianathan Ravi1, Wei-Ping Yu2, Nisha E. Pillai1, Michelle M. Lian1, Boon-Hui Tay1, Sumanty Tohari1, Sydney Brenner1,3, and Byrappa Venkatesh1
1 Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore 138673
2 Animal Gene Editing Laboratory, Biological Resource Centre, A*STAR, Singapore 138673.
3 Okinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa 904-0495, Japan
Published online in Mol. Biol. Evol. on 5 Nov 2015.
The brain, comprising billions of neurons and intricate neural networks, is the most complex organ in vertebrates. This complexity is conferred by the enormous diversity of individual neurons in the vertebrate brain. In jawed vertebrates such as mammals, bony fishes and sharks, it has been shown that clustered protocadherins provide the molecular basis for the neuronal diversity and complexity of the brain. This is achieved through stochastic and combinatorial expression of various isoforms of clustered protocadherins in individual neurons. It is estimated that clustered protocadherins can generate more than 3×1010 possible variations in each neuron. Invertebrate chordates possess a simple neural tube lacking overt partitions and contain only non-clustered protocadherins. The presence of clustered protocadherins is thus indicative of a complex neuronal system. The living jawless vertebrates comprising lampreys and hagfish, collectively known as cyclostomes, also possess complex brains like jawed vertebrates. However, it is unclear whether they possess clustered protocadherins that can generate the enormous neuronal diversity seen in jawed vertebrates. Based on analyses of genome assemblies of two lamprey species, the Japanese lamprey (Lethenteron japonicum) and the sea lamprey (Petromyzon marinus), transcriptomes from the brain of adult Japanese lamprey and early developmental stage embryos (st23 to 28) of the sea lamprey, and brain ESTs of the inshore hagfish (Eptatretus burgeri), we have shown that lampreys and hagfish possess majority of the non-clustered protocadherins present in jawed vertebrates but lack the clustered protocadherins. Our findings indicate that the clustered protocadherins originated from a non-clustered protocadherin in the jawed vertebrate ancestor, after the two rounds of whole-genome duplication. The absence of clustered protocadherins in lamprey and hagfish raises the possibility that this ancient group of vertebrates might have evolved novel molecules or mechanisms for generating neuronal diversity.
(A) The clustered protocadherin locus in human showing a schematic of the alternative isoforms that can be generated from the Pcdh-α locus. Through alternative splicing and stochastic expression, the isoforms of human clustered protocadherin genes can generate 3×1010 possible variations in each neuron. (B) Distribution of non-clustered and clustered protocadherin genes in different chordate groups.
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