DNA endoreplication: what you did not expect from neurons

Endoreplication has been repeatedly found in eukaryotes. In particular, endoreplicative or endoduplicative mechanisms have been reported in protists, plants, arthropods, molluscs, fishes and mammals. The same studies indicated that cells possessing endoreplicated genome are generally large-sized and highly metabolically active, suggesting that endoreplication could have a functional significance. Neurons are typically considered as fully differentiated, non-dividing cells containing normally a diploid DNA amount, and endoreplication has not been historically reported in neuronal cells. Despite this general rule, some papers questioned the validity of this finding and indicated that giant neurons in molluscs, supramedullary and hypothalamic magnocellular neurons in fishes and Purkinje cells in vertebrate (prevalently mammal) cerebellum present DNA contents greater than 2C. Quantitative microfluorometric evaluation of DNA content in nerve cells of the gastropod molluscs Planorbarius corneus, Aplysia californica and Lymnaea stagnalis indicated that neuronal DNA contents are scattered between 2C and 200.000C values. This increase in DNA content is given in account mostly to whole-genome duplications, whereas in P. corneus an endoreplication mainly of GC-rich sequences occurs. The second example of endoreplicated neurons was highlighted in the large clustered neurons, located at the boundary between the medulla oblongata and spinal cord, of the fishes Lophius piscatorius and Diodon holacanthus. The DNA content of these neurons, evaluated by microfluorimetric methods, results ranging from a minimum of 4C in the smaller to over 5000C in the larger neurons. Further experiments with AT and GC specific fluorochromes showed that the increase in DNA content is due to an amplification involving GC-rich DNAs in L. piscatorius, whereas a whole-genome endoduplication occurs in D. holacanthus. Subsequent quantitative evaluation revealed that also L. piscatorius hypothalamic magnocellular neurons, located in the preoptic and tuberal complexes, largely exceed 2C DNA content. The last example is represented by nuclei of vertebrate Purkinje cells isolated from cerebellum. These results have been debated for several years, since contrasting data are present in literature. Up till now, the dilemma remains unsolved, but it is not possible to exclude that a small percentage of Purkinje neurons contains hyperdiploid and tetraploid nuclei, might be due to an extra DNA synthesis. In order to go in depth in the understanding of this topic, we revised in the present review the available data about endoreplication in invertebrate and vertebrate giant neurons and considered the possible molecular mechanisms responsible for endoreplication. Furthermore, some possible functional significances of neuron endoploidy are discussed.