Hippocampal neurons develop numerous dendritic spines along their dendritic shafts during two weeks in culture (top). Silencing of one of the ORC subunits, ORC3, with siRNA, leads to a dramatic loss of dendritic spines in treated neurons (bottom).

The origin recognition complex (ORC), which is responsible for regulating DNA replication during the cell cycle, has a curious role in postmitotic neurons. Writing in the Journal of Cell Biology, Huang and colleagues show that the ORC subunits are expressed in the adult mouse brain and are crucial for dendrite and spine development.

The ORC is a hexameric protein that acts as a cyclin-dependent kinase (CDK)-regulated, ATPase-dependent molecular switch for initiating DNA replication during the cell cycle, ensuring that each wave of CDK activation is translated into one, and only one, round of genome replication. Adult neurons are mostly postmitotic and have no need for DNA replication, so it was a surprise when Huang et al. found that the Orc genes appeared frequently in the adult mouse brain database.

To explore their finding, the researchers studied Orc expression and found that the Orc2–6 mRNAs were abundant in adult brain tissues such as the cerebral cortex, hippocampus and cerebellum. Interestingly, Orc3 is expressed in the cytoplasm of cultured hippocampal neurons, rather than in the nucleus as one would expect, and the expression co-localizes with the dendritic marker microtubule-associated protein 2 (MAP2).

What is the function of ORC in postmitotic neurons? To address this issue, Huang et al. silenced Orc expression in cultured hippocampal neurons using small interfering RNAs (siRNAs). Cultured hippocampal neurons undergo two stages of development: the initial arborization of dendrites at about 7–10 days in vitro (DIV) followed by the elaboration of spines at about 14–17 DIV.

In hippocampal neurons, silencing either Orc3 or Orc5 expression at 7 DIV results in the development of shorter dendrites with severely reduced branching. Similar manipulation of Orc expression at 14 DIV leads to a dramatic decrease in the density of spines along dendrites. These results suggest that the ORC is necessary for dendrite and spine development.

Three of the ORC subunits — ORC1, ORC4 and ORC5 — belong to a family of ATPases. It seems that the ORC's ATPase activity negatively regulates dendrite elaboration, as hippocampal neurons overexpressing a mutant ORC4 with defective ATP binding and hydrolysis show a significant increase in dendritic branching.

This newly discovered role of the ORC in dendrite and spine development is intriguing. The ORC might be a key part of the molecular machinery that translates patterns of neural activity into patterns of neuronal connectivity, a process that underlies long-term plasticity and memory.